Alpha-7 NICOTINIC ACETYLCHOLINE RECEPTOR MODULATORS AND USES THEROF-I

ABSTRACT

The present invention relates to chemical compounds of formula (I), with the substituents as described in the specification, useful in the positive modulation of the alpha 7 nicotinic acetylcholine receptor (α7 nAChR). The invention also relates to the use of these compounds in the treatment or prevention of a broad range of diseases in which the positive modulation of α7 nAChR is advantageous, including neurodegenerative and neuropsychiatric diseases and also neuropathic pain and inflammatory diseases.

FIELD OF THE INVENTION

The present invention relates to chemical compounds useful in thepositive modulation of the alpha 7 nicotinic acetylcholine receptor (α7nAChR). The invention also relates to the use of these compounds in thetreatment or prevention of a broad range of diseases in which thepositive modulation of α7 nAChR is advantageous, includingneurodegenerative and neuropsychiatric diseases and also neuropathicpain and inflammatory diseases.

BACKGROUND

The α7 nAChRs are rapidly desensitizing ligand-gated ion channels thatare abundantly expressed in the cerebral cortex and the hippocampus, alimbic structure intimately linked to attention processing and memoryformation. α7 nAChRs modulate neurotransmitter release and areresponsible for direct fast excitatory neurotransmission. At thecellular level, activation of α7 nAChRs can regulate interneuronexcitability, modulate the release of excitatory and inhibitoryneurotransmitters, and contribute to neuroprotective effects.

Several lines of evidence indicate that impaired attention andcognition, which are characteristic of neurological and psychiatricdisorders such as Alzheimer's disease (AD), schizophrenia, Parkinson'sdisease (PD), multiple sclerosis, attention deficit hyperactivitydisorder (ADHD), mild cognitive impairment (MCI), age associated memoryimpairment (AAMI), may involve degeneration or hypo-function ofcholinergic input. Moreover, genetic linkage has identified α7 AChRs asa predisposing factor related to sensory gating deficits. Thus,targeting the α7 nAChRs represents a therapeutic strategy forameliorating cognitive deficits associated with neurodegenerative andneuropsychiatric diseases.

A number of reports also suggest that α7 nAChRs mediate protectionagainst neurotoxicity induced by amyloid beta and excitotoxic insults.Peripherally, α7 nAChRs are expressed in macrophages and theirstimulation is essential for inhibiting the release of proinflammatorycytokines (e.g. TNF-α, IL-1) via the cholinergic anti-inflammatorypathway which is triggered in response to signals from the vagus nerve.Thus, the clinical use of positive modulators of the α7 nAChRs couldalso represent a strategy against inflammatory diseases.

A growing body of evidence indicates the role of the alpha7 nicotinicreceptor subtype in neuropathic pain. Both agonists and positiveallosteric modulators have been shown to play an important role inchronic inflammatory and neuropathic pain signaling and to attenuateneuropathic pain in preclinical models.

Selective positive allosteric modulation (PAM) of the α7 nAChR is arecently proposed therapeutic approach for treating these diseasestates. A key advantage of this approach is that modulation only occursin the presence of endogenous agonist thereby preserving the temporaland spatial integrity of neurotransmission. Several different profileshave been described for PAMs of the α7 nAChR ranging from Type Imodulators that predominately affect the peak current and may alsoincrease channel affinity for the agonist, to Type II modulators thataffect the peak current, delay the desensitization of the receptor andmay reactivate desensitized receptors. Several PAMs have been describedin the literature with some Type I examples including 5-Hydroxyindole,NS-1738, Ivermectin, Galantamine and Genistein; Type II examplesincluding PNU-120596, TQS and A-867744 and some intermediate examplesbeing SB-206553 and JNJ-1930942. All PAMs demonstrate enhanced receptorresponses to the endogenous ligands acetylcholine and choline, as wellas to nicotine and other agonists.

The present invention seeks to address some of the shortcomings of theprior art therapeutics and is directed to a new class of compounds whichexhibit positive modulation of α7 nAChR.

SUMMARY OF THE INVENTION

In one aspect the invention provides compounds of formula (I) or saltsthereof:

wherein

-   -   R₁ is selected from optionally substituted aryl, optionally        substituted benzyl, optionally substituted heteroaryl, or        optionally substituted heterocyclyl;    -   R₂ is selected from hydrogen, C₁-C₄ alkyl, F, Cl, CN, phenyl or        C₁-C₄ haloalkyl;    -   R₃ is selected from hydrogen, C₁-C₄ alkyl, F, Cl, CN, or C₁-C₄        haloalkyl; or    -   R₂ and R₃ together form C₄₋₉ cycloalkyl or C₄₋₉ cycloalkenyl;    -   R₄ is selected from optionally substituted heteroaryl,        optionally substituted heterocyclyl, or optionally substituted        aryl;    -   R₅ is selected from hydrogen or C₁-C₄ alkyl;    -   R₆-R₈ are independently selected from halogen or hydrogen; and    -   n is 1-3,    -   wherein when R₂ and R₃ are hydrogen, and n is 1, R₁ is not (1)        phenyl or phenyl substituted with cyclohexyl, heterocyclyl, F or        OCH₃; or (2) optionally substituted heteroaryl.

In an embodiment R₁ is selected from an optionally substituted aryl,optionally substituted heteroaryl, or optionally substitutedheterocyclyl.

In an embodiment R₁ is an optionally substituted aryl group and morepreferably an optionally substituted phenyl group.

Accordingly, in a further aspect the invention provides compounds offormula (Ia) or salts thereof:

wherein

-   -   R_(1a) is selected from the group consisting of optionally        substituted lower alkyl, optionally substituted aryl, optionally        substituted aryloxy, optionally substituted heteroaryl,        optionally substituted heterocyclyl, —P═O(OH)(NH₂), —C(O)NR′R′,        —NR′S(O)₂NR′R′, —NR′—S(O)₂R′, —NR′C(O)R′, —S(O)₂—NR′R′ and        —NR′R′ (where each R′ is independently selected from hydrogen,        lower alkyl, C₃-C₇ cycloalkyl, heterocyclyl, heteroaryl, —OH, or        NH₂), —S(O)R″ (where R″ is lower alkyl, or cycloalkyl), and        —S(O)₂R′″ (where R′″ is lower alkyl, or cycloalkyl);    -   each R_(1b) is independently selected from the group consisting        of cyano, halo, nitro, optionally substituted lower alkyl,        optionally substituted aryl, optionally substituted aryloxy,        optionally substituted arylalkyl, optionally substituted        heteroaryl, optionally substituted heterocyclyl, optionally        substituted C₃₋₇ cycloalkyl, —P═O(OH)(NH₂), —OR, —C(O)R,        —C(O)OR, —OC(O)R (where R is selected from hydrogen, optionally        substituted alkyl, optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted C₃₋₇ cycloalkyl,        optionally substituted heterocyclyl, optionally substituted        heteroaryl, and optionally substituted aryl), —C(O)NR′R″,        —NR′C(O)R″, —S(O)₂—NR′R″ and —NR′R″ (where R′ and R″ are        independently selected from hydrogen or lower alkyl), —S(O)R′″        (where R′″ is lower alkyl, or cycloalkyl), —S(O)₂R′″ (where R′″        is lower alkyl, cycloalkyl or OH), or any two adjacent R_(1b) or        R_(1a) and R_(1b) together form heterocyclyl or heteroaryl;    -   z is 0-4;    -   R₂ is selected from hydrogen, C₁-C₄ alkyl, F, Cl, CN, phenyl or        C₁-C₄ haloalkyl;    -   R₃ is selected from hydrogen, C₁-C₄ alkyl, F, Cl, CN, or C₁-C₄        haloalkyl; or    -   R₂ and R₃ together form C₄-C₉ cyclo alkyl or C₄-C₉ cycloalkenyl;    -   R₄ is selected from optionally substituted heteroaryl,        optionally substituted heterocyclyl, or optionally substituted        aryl;    -   R₅ is selected from hydrogen or C₁-C₄ alkyl;    -   R₆-R₈ are independently selected from halogen or hydrogen; and    -   n is 1-3.

In an embodiment z is 1.

In an embodiment z is 2.

In an embodiment z is 0.

In an embodiment z is 0 and R_(1a) is in the para position.

In an embodiment R_(1a) is independently selected from the groupconsisting of optionally substituted lower alkyl, optionally substitutedaryl, optionally substituted aryloxy, optionally substituted heteroaryl,optionally substituted heterocyclyl, —P═O(OH)(NH₂), —C(O)NR′R′,—NR′S(O)₂NR′R′, —NR′—S(O)₂R′, —NR′C(O)R′, —S(O)₂—NR′R′ and —NR′R′ (whereeach R′ is independently selected from hydrogen, lower alkyl, C₃-C₇cycloalkyl, heterocyclyl, heteroaryl, —OH, NH₂), —S(O)R″ (where R″ islower alkyl, or cycloalkyl), and —S(O)₂R′″ (where R′″ is lower alkyl, orcycloalkyl).

In another embodiment R₂ is C₁-C₃ alkyl and R₃ is C₁-C₃ alkyl.

In another embodiment R₃ and R₂ together form a C₄-C₉ cycloalkyl.

Accordingly, in a further aspect the invention provides compounds offormula (Ib) or salts thereof:

wherein

-   -   R₁ is selected from optionally substituted aryl, optionally        substituted benzyl, optionally substituted heteroaryl or        optionally substituted heterocyclyl;    -   R₂ and R₃ together form C₄₋₉ cycloalkyl;    -   R₄ is selected from optionally substituted heteroaryl,        optionally substituted heterocyclyl, or optionally substituted        aryl;    -   R₅ is selected from hydrogen or C₁-C₄ alkyl;    -   R₆-R₈ are independently selected from halogen or hydrogen; and    -   n is 1-3.

Accordingly, in a further aspect the invention provides compounds offormula (Ic) or salts thereof:

wherein

-   -   R₁ is selected from optionally substituted aryl, optionally        substituted benzyl, optionally substituted heteroaryl or        optionally substituted heterocyclyl;    -   R₂ and R₃ each independently represent C₁-C₃ alkyl;    -   R₄ is selected from optionally substituted heteroaryl,        optionally substituted heterocyclyl, or optionally substituted        aryl;    -   R₅ is selected from hydrogen or C₁-C₄ alkyl;    -   R₆-R₈ are independently selected from halogen or hydrogen; and    -   n is 1-3.

In an embodiment R₁ in (Ib) and (Ic) is a phenyl group substituted withR_(1a) wherein R_(1a) is selected from the group consisting ofoptionally substituted lower alkyl, optionally substituted aryl,optionally substituted aryloxy, optionally substituted heteroaryl,optionally substituted heterocyclyl, —P═—O(OH)(NH₂), —C(O)NR′R′,—NR′S(O)₂NR′R′, —NR′—S(O)₂R′, —NR′C(O)R′, —S(O)₂—NR′R′ and —NR′R′ (whereeach R′ is independently selected from hydrogen, lower alkyl, C₃-C₇cycloalkyl, heterocyclyl, heteroaryl, —OH, or NH₂), —S(O)R″ (where R″ islower alkyl, or cycloalkyl), or —S(O)₂R′″ (where R′″ is lower alkyl, orcycloalkyl).

In a further aspect the invention provides a method for the treatment orprevention of cognitive deficits associated with neurodegeneration orneuropsychiatric diseases, said method including the step ofadministering a compound of formula (I), (Ia), (Ib) or (Ic), or apharmaceutically acceptable salt thereof, or a composition comprising acompound of formula (I), (Ia), (Ib) or (Ic), and related formulae asherein defined or a pharmaceutically acceptable salt thereof.

In still a further aspect the invention provides a method for thetreatment or prevention of inflammatory diseases, said method includingthe step of administering a compound of formula (I), (Ia), (Ib) or (Ic),and related formulae as herein defined or a pharmaceutically acceptablesalt thereof, or a composition comprising a compound of formula (I),(Ia), (Ib) or (Ic), and related formulae as herein defined or apharmaceutically acceptable salt thereof.

In still a further aspect the invention provides a method for thetreatment or prevention of neuropathic pain, said method including thestep of administering a compound of formula (I), (Ia), (Ib) or (Ic), andrelated formulae as herein defined or a pharmaceutically acceptable saltthereof, or a composition comprising a compound of formula (I), (Ia),(Ib) or (Ic), and related formulae as herein defined or apharmaceutically acceptable salt thereof.

In another aspect the invention provides the use of a compound offormula (I), (Ia), (Ib) or (Ic), and related formulae as herein definedor a salt thereof in the manufacture of a medicament for the treatmentor prevention of cognitive deficits associated with neurodegeneration orneuropsychiatric diseases.

In another aspect the invention provides the use of a compound offormula (I), (Ia), (Ib) or (Ic), and related formulae as herein definedor a salt thereof in the manufacture of a medicament for the treatmentor prevention of inflammatory diseases.

In another aspect the invention provides the use of a compound offormula (I), (Ia), (Ib) or (Ic), and related formulae as herein definedor a salt thereof in the manufacture of a medicament for the treatmentor prevention of neuropathic pain.

In another aspect of the invention there is provided a method ofpositively modulating α7nAChRs in a cell by contacting the cell with acompound of formula (I), (Ia), (Ib) or (Ic), and related formulae asherein defined or a pharmaceutically acceptable salt thereof, to saidcell.

In a further aspect of the invention there is provided a pharmaceuticalcomposition for use as a neuroprotective agent, the compositioncomprising an effective amount of a compound of formula (I), (Ia), (Ib)or (Ic), and related formulae as herein defined or a pharmaceuticallyacceptable salt thereof and optionally a carrier or diluent.

In still a further aspect of the invention there is provided apharmaceutical composition for use as an anti-inflammatory agent, thecomposition comprising an effective amount of a compound of formula (I),(Ia), (Ib) or (Ic), and related formulae as herein defined or apharmaceutically acceptable salt thereof and optionally a carrier ordiluent.

In still a further aspect of the invention there is provided apharmaceutical composition for treating neuropathic pain, thecomposition comprising an effective amount of a compound of formula (I),(Ia), (Ib) or (Ic), and related formulae as herein defined or apharmaceutically acceptable salt thereof and optionally a carrier ordiluent.

In another aspect of the invention there is provided a process for thepreparation of compounds of formula (I), (Ia), (Ib) or (Ic), and relatedformulae as herein defined or salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The term “alkyl” as used alone or in combination herein refers to astraight or branched chain saturated hydrocarbon group. The term “C₁₋₁₂alkyl” refers to such a group containing from one to twelve carbon atomsand “lower alkyl” refers to C₁₋₆ alkyl groups containing from one to sixcarbon atoms, such as methyl (“Me”), ethyl (“Et”), n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl and the like.

The term “cycloalkyl” refers to non-aromatic, saturated non-aromaticcarbocycles. The term “C₄₋₉ cycloalkyl”, for instance, refers to such agroup having from 4 to 9 carbon atoms. Examples include cyclobutyl,cyclopentyl and cyclohexyl.

The term “alkenyl” refers to a straight or branched hydrocarboncontaining one or more double bonds, preferably one or two double bonds.The term “C₂₋₁₂ alkenyl”, for instance, refers to such a groupcontaining from two to twelve carbon atoms. Examples of alkenyl includeallyl, 1-methylvinyl, butenyl, iso-butenyl, 1, 3-butadienyl,3-methyl-2-butenyl, 1,3-butadienyl, 1,4-pentadienyl, 1-pentenyl,1-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl and1,3,5-hexatrienyl.

The term “cycloalkenyl” refers to cyclic alkenyl groups having a singlecyclic ring or multiple condensed rings, and at least one point ofinternal unsaturation, preferably incorporating 4 to 11 carbon atoms.Examples of suitable cycloalkenyl groups include, for instance,cyclobut-2-enyl, cyclopent-3-enyl, cyclohex-4-enyl, cyclooct-3-enyl,indenyl and the like.

The term “alkynyl” refers to a straight or branched hydrocarboncontaining one or more triple bonds, preferably one or two triple bonds.The term “C₂₋₁₂ alkynyl”, for instance, refers to such a groupcontaining from two to twelve carbon atoms. Examples include 2-propynyland 2- or 3-butynyl.

The term “alkoxy” as used alone or in combination refers to a straightor branched chain alkyl group covalently bound via an oxygen linkage(—O—) and the terms “C₁₋₆ alkoxy” and “lower alkoxy” refer to suchgroups containing from one to six carbon atoms, such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, t-butoxy and the like.

The term “aryl” refers to carbocyclic (non-heterocyclic) aromatic ringsor ring systems. The aromatic rings may be mono- or bi-cyclic ringsystems. The aromatic rings or ring systems are generally composed of 5to 10 carbon atoms. Examples of suitable aryl groups include but are notlimited to phenyl, biphenyl, naphthyl, tetrahydronaphthyl, and the like.

Preferred aryl groups include phenyl, naphthyl, indenyl, azulenyl,fluorenyl or anthracenyl.

The term “heteroaryl” refers to a monovalent aromatic carbocyclic group,preferably of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selectedfrom oxygen, nitrogen and sulfur within the ring. Preferably theheteroatom is nitrogen. Such heteroaryl groups can have a single ring(e.g., pyridyl, pyrrolyl or furyl) or multiple condensed rings (e.g.,indolizinyl, benzothienyl, or benzofuranyl).

The term “heterocyclyl” refers to a monovalent saturated or unsaturatedgroup having a single ring or multiple condensed rings, preferably from1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen,sulfur, oxygen, selenium or phosphorous within the ring.

Examples of 5-membered monocyclic heterocyclyl and heteroaryl groupsinclude furyl, thienyl, pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl,oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4 oxadiazolyls)thiazolyl, isoxazolyl, furazanyl, isothiazolyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and1,3,4 triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4thiadlazolyls).

Examples of 6-membered monocyclic heterocyclyl and heteroaryl groupsinclude pyridyl, pyrimidinyl, pyridazinyl, pyranyl, pyrazinyl,piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl,1,3,5-trithianyl and triazinyl.

Examples of 8, 9 and 10-membered bicyclic heterocyclyl and heteroarylgroups include 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl, indolyl,isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl,isoquinolinyl, quinolinyl, quinoxalinyl, uridinyl, purinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl,naphthyridinyl, pteridinyl and the like.

The term “arylalkyl” refers to carbocyclic aromatic rings or ringsystems as previously described and substituted by an alkyl group, alsoas previously described. Unless otherwise indicated the aryl substituentis attached by the alkyl part of the substituent. An example of anarylalkyl group is a benzyl group. Likewise the terms “aryl C₁₋₁₂alkyl”, “aryl C₂₋₁₂ alkenyl” and “aryl C₂₋₁₂ alkynyl” refer tocarbocyclic aromatic rings or ring systems as previously described andsubstituted by a C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl or C₂₋₁₂ alkynyl group, aspreviously described.

The terms “halo” and “halogen” refers to fluoro, chloro, bromo and iodogroups.

The term “halo alkyl” group has one or more of the hydrogen atoms on analkyl group replaced with halogens. Notable examples are —CF₃ or —CF₂H.

The term “aryloxy” refers to an aryl group as earlier described linkedto the parent structure via an oxygen linkage (—O—). A notable exampleis phenoxy. Similarly the term “heteroaryloxy” refers to a heteroarylgroup as earlier described linked to the parent structure via an oxygengroup. A notable example is a 4, 6 or 7-benzo[b]furanyloxy group.

The term “optionally substituted” means that a group may include one ormore substituents. One or more hydrogen atoms on the group may bereplaced by substituent groups independently selected from halogens (forexample halo alkyl such as —CF₃ or —CF₂H), C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, —(CH₂)_(p)C₃₋₇ cycloalkyl, —(CH₂)_(p)C₄₋₇ cycloalkenyl,—(CH₂)_(p) aryl, —(CH₂)_(p) heterocyclyl, —(CH₂)_(p) heteroaryl,—C₆H₄S(O)_(q)C₁₋₆ alkyl, —C(Ph)₃, —CN, —O—(CH₂)₁₋₆—R, —O—(CH₂)₁₋₆—OR,—OC(O)R, —C(O)R, —C(O)OR, —OC(O)NR′R″, —NR′R″, —NRC(O)R′, —NRC(O)NR′R″,—NRC(S)NR′R″, —NRS(O)₂R′, —NRC(O)OR′, —C(NR)NR′R″, —C(═NOR′)R,—C(═NOH)NR′R″, —C(O)NR′R″, —C(═NCN)—NR′R″, —C(═NR)NR′R″, —C(═NR′)SR″,—NR′C(═NCN)SR″, —CONRSO₂R′, —C(S)NR′R″, —S(O)_(q)R, —SO₂NR′R″,—SO₂NRC(O)R′, —OS(O)₂R, —PO(OR)₂ and —NO₂;

where p is 0-6, q is 0-2 and each R, R′ and R″ is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, aryl, heterocyclyl, heteroaryl, C₁₋₆ alkylaryl, C₁₋₅alkylheteroaryl, and C₁₋₆ alkylheterocyclyl, wherein the alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, C₁₋₆alkylaryl, C₁₋₆ alkylheteroaryl, or C₁₋₆ alkylheterocyclyl, may beoptionally substituted with one to six of same or different groupsselected from halogen, hydroxy, lower alkyl, lower alkoxy, —CO₂H, CF₃,CN, phenyl, NH₂ and —NO₂; or when R′ and R″ are attached to the samenitrogen atom, they may, together with the atom to which they areattached, form a 5 to 7 membered nitrogen containing heterocyclic ring.

A list of preferred optional substituents Includes: halogen (inparticular, Cl, Br or F), C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl (in particular —CF₃), C₁₋₆ haloalkoxy (such as—OCF₃), —OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, —NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄ alkyl)₂, —CN, —NO₂, mercapto, —P═O(OH)(NH₂). —S(O)₂NH₂,—S(O)₂NHC₁₋₄ alkyl, —S(O)₂N(C₁₋₄ alkyl)₂, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, CO₂H, —S(O)R′″ (where R′″ is lower alkyl or cycloalkyl)and —S(O)₂R′″ (where R′″ is lower alkyl, cycloalkyl or OH).

Unless otherwise defined and only in respect of the ring atoms ofnon-aromatic carbocyclic or heterocyclic compounds, the ring atoms ofsuch compounds may also be optionally substituted with one or two ═Ogroups, instead of or in addition to the above described optionalsubstituents.

When the optional substituent is or contains an alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl or heterocyclyl group, the group may itselfbe optionally substituted with one to six of the same or differentsubstituents selected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl (in particular —CF₃), C₁₋₆haloalkoxy (such as —OCF₃), —OH, phenyl, benzyl, phenoxy, benzyloxy,benzoyl, —NH₂, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, —CN, —NO₂, mercapto,—P═O(OH)(NH₂), —S(O)₂NH₂, —S(O)₂NHC₁₋₄ alkyl, —S(O)₂N(C₁₋₄ alkyl)₂, C₁₋₆alkylcarbonyl, C₁₋₆ alkoxycarbonyl, CO₂H, —S(O)R′″ (where R′″ is loweralkyl or cycloalkyl) and —S(O)₂R′″ (where R′″ is lower alkyl, cycloalkylor OH).

In an embodiment and with specific reference to compounds of formulae(I), (Ia), or (Ib) R₂ is selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl,phenyl, F or Cl, and R₃ is selected from hydrogen, C₁-C₄ alkyl, C₁-C₄haloalkyl, or F, Cl, or CN, or R₂ and R₃ together form C₄₋₉ cycloalkylor C₄₋₉ cycloalkenyl.

In an embodiment R₆-R₈ are hydrogen.

Accordingly, in another aspect the Invention provides compounds offormula (I′), or salts thereof:

wherein

-   -   R₁ is selected from optionally substituted aryl, optionally        substituted benzyl, optionally substituted heteroaryl, or        optionally substituted heterocyclyl;    -   R₂ is selected from C₁-C₄ alkyl, F, Cl, phenyl or C₁-C₄        haloalkyl;    -   R₃ is selected from hydrogen, C₁-C₄ alkyl, F, Cl, CN, or C₁-C₄        haloalkyl; or    -   R₂ and R₃ together form C₄₋₉ cycloalkyl or C₄₋₉ cycloalkenyl;    -   R₄ is selected from optionally substituted heteroaryl,        optionally substituted heterocyclyl, or optionally substituted        aryl;    -   R₅ is selected from hydrogen or C₁-C₄ alkyl; and    -   n is 1-3.

Also, in another aspect the invention provides compounds of formula(Ia′), or salts thereof:

wherein

-   -   each R_(1a) is independently selected from the group consisting        of optionally substituted lower alkyl, optionally substituted        aryl, optionally substituted aryloxy, optionally substituted        heteroaryl, optionally substituted heterocyclyl, —P═O(OH)(NH₂),        —C(O)NR′R′, —NR′S(O)₂NR′R′, —NR′—S(O)₂R′, —NR′C(O)R′,        —S(O)₂—NR′R′ and —NR′R′ (where each R′ is independently selected        from hydrogen, lower alkyl, C₃-C₇ cycloalkyl, heterocyclyl,        heteroaryl, —OH, or NH₂), —S(O)R″ (where R″ is lower alkyl, or        cycloalkyl), —S(O)₂R′″ (where R′″ is lower alkyl, or        cycloalkyl), or any two adjacent R_(1a) together form        heterocyclyl or heteroaryl;    -   m is 0-5;    -   R₂ is selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, phenyl, F, or        Cl;    -   R₃ is selected from hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, F,        Cl, or CN; or    -   R₂ and R₃ together form C₄₋₉ cycloalkyl or C₄₋₉ cycloalkenyl;    -   R₄ is selected from optionally substituted heteroaryl,        optionally substituted heterocyclyl, or optionally substituted        aryl;    -   R₅ is independently selected from hydrogen, or C₁-C₄ alkyl; and    -   n is 1-3.

In relation to the aforementioned compounds the following definitionsmay also apply:

-   -   a) R₂ and R₃ are both C₁-C₃ alkyl (preferably methyl), or R₂ and        R₃ together form a C₄-C₉ cycloalkyl ring.    -   R₂ and R₃ are both F.    -   c) R₂ and R₃ are both methyl.    -   d) R₂ is methyl, and R₃ is hydrogen.    -   e) R₂ and R₃ together form a C₄-C₉ cycloalkyl ring, preferably        cyclopentyl or cyclohexyl ring.

In relation to the aforementioned compounds the following furtheradditional definitions may also apply:

-   -   f) R₂ and R₃ are both independently C₁-C₃ alkyl (preferably        methyl), or both F, or R₂ and R₃ together, form a C₄-C₉        cycloalkyl ring, and R₄ is selected from heteroaryl or aryl each        of which may be independently substituted by one to three        substituents selected from halogen (in particular, Cl, Br or F),        C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl (in particular —CF₃), C₁₋₆ haloalkoxy (such as —OCF₃),        —OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, —NHC₁₋₄ alkyl,        —N(C₁₋₄alkyl)₂, —CN, —S(O)₂NH₂, —S(O)₂NHC₁₋₄ alkyl, —S(O)₂N(C₁₋₄        alkyl)₂, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, —S(O)R′″        (where R′″ is lower alkyl or cycloalkyl) and —S(O)₂R′″ (where        R′″ is lower alkyl, or cycloalkyl).    -   g) R₂ and R₃ are both CH₃, and R₄ is selected from heteroaryl or        aryl each of which may be independently substituted by one to        three substituents selected from halogen (in particular, Cl, Br        or F), C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl (in particular —CF₃), C₁₋₆ haloalkoxy (such as —OCF₃),        —OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, —NHC₁₋₄ alkyl,        —N(C₁₋₄ alkyl)₂, —CN, —S(O)₂NH₂, —S(O)₂NHC₁₋₄ alkyl,        —S(O)₂N(C₁₋₄ alkyl)₂, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl,        —S(O)R′″ (where R′″ is lower alkyl or cycloalkyl) and —S(O)₂R′″        (where R′″ is lower alkyl, or cycloalkyl).    -   h) R₂ is methyl, R₃ is hydrogen, and R₄ is selected from        heteroaryl or aryl each of which may be independently        substituted by one to three substituents selected from halogen        (in particular, Cl, Br or F), C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl (in particular —CF₃), C₁₋₆        haloalkoxy (such as —OCF₃), —OH, phenyl, benzyl, phenoxy,        benzyloxy, benzoyl, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, —CN,        —S(O)₂NH₂, —S(O)₂NHC₁₋₄ alkyl, —S(O)₂N(C₁₋₄ alkyl)₂, C₁₋₆        alkylcarbonyl, C₁₋₆ alkoxycarbonyl, —S(O)R′″ (where R′″ is lower        alkyl or cycloalkyl) and —S(O)₂R′″ (where R′″ is lower alkyl, or        cycloalkyl).    -   i) R₂ and R₃ together, form a C₄-C₉ cycloalkyl ring, preferably        cyclopentyl or cyclohexyl ring, and R₄ is selected from        heteroaryl or aryl each of which may be independently        substituted by one to three substituents selected from halogen        (in particular, Cl, Br or F), C₁₋₈ alkyl, C₁₋₆ alkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl (in particular —CF₃), C₁₋₆        haloalkoxy (such as —OCF₃), —OH, phenyl, benzyl, phenoxy,        benzyloxy, benzoyl, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, —CN,        —S(O)₂NH₂, —S(O)₂NHC₁₋₄ alkyl, —S(O)₂N(C₁₋₄ alkyl)₂, C₁₋₆        alkylcarbonyl, C₁₋₆ alkoxycarbonyl, —S(O)R′″ (where R′″ is lower        alkyl or cycloalkyl) and —S(O)₂R′″ (where R′″ is lower alkyl, or        cycloalkyl).

In relation to the aforementioned compounds of formulae (Ia) and (Ia′)the following additional definitions may also apply:

-   -   j) R₂ and R₃ are both independently C₁-C₃ alkyl (preferably        methyl), or both F, or R₂ and R₃ together, form a C₄-C₉        cycloalkyl ring, and R₄ is selected from heteroaryl or aryl each        of which may be independently substituted by one to three        substituents selected from halogen (in particular, Cl, Br or F),        C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl (in particular —CF₃), C₁₋₆ haloalkoxy (such as —OCF₃),        —OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, —NHC₁₋₄ alkyl,        —N(C₁₋₄ alkyl)₂, —CN, —S(O)₂NH₂, —S(O)₂NHC₁₋₄ alkyl,        —S(O)₂N(C₁₋₄ alkyl)₂, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl,        —S(O)R′″ (where R′″ is lower alkyl or cycloalkyl) and —S(O)₂R′″        (where R′″ is lower alkyl, or cycloalkyl), and m is 1 or 2, and        each R_(1a) is independently selected from the group consisting        of optionally substituted lower alkyl, optionally substituted        aryl, optionally substituted aryloxy, optionally substituted        heteroaryl, optionally substituted heterocyclyl, —P═O(OH)(NH₂),        —C(O)NR′R′, —NR′S(O)₂NR′R′, —NR′—S(O)₂R′, — NR′C(O)R′,        —S(O)₂—NR′R′ and —NR′R′ (where each R′ is independently selected        from hydrogen, lower alkyl, C₃-C₇ cycloalkyl, heterocyclyl,        heteroaryl, —OH, or NH₂), —S(O)R″ (where R″ is lower alkyl, or        cycloalkyl), —S(O)₂R′″ (where R′″ is lower alkyl, or        cycloalkyl), or any two adjacent R_(1a) together form        heterocyclyl or heteroaryl.    -   k)R₂ and R₃ are both CH₃, and R₄ is selected from heteroaryl or        aryl each of which may be independently substituted by one to        three substituents selected from halogen (in particular, Cl, Br        or F), C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl (in particular —CF₃), C₁₋₆ haloalkoxy (such as —OCF₃),        —OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, —NHC₁₋₄ alkyl,        —N(C₁₋₄ alkyl)₂, —CN, —S(O)₂NH₂, —S(O)₂NHC₁₋₄ alkyl,        —S(O)₂N(C₁₋₄ alkyl)₂, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl,        —S(O)R′″ (where R′″ is lower alkyl or cycloalkyl) and —S(O)₂R′″        (where R′″ is lower alkyl, or cycloalkyl), and m is 1 or 2, and        each R_(1a) is independently selected from the group consisting        of optionally substituted lower alkyl, optionally substituted        aryl, optionally substituted aryloxy, optionally substituted        heteroaryl, optionally substituted heterocyclyl, —P═O(OH)(NH₂),        —C(O)NR′R′, —NR′S(O)₂NR′R′, —NR′—S(O)₂R′, —NR′C(O)R′,        —S(O)₂—NR′R′ and —NR′R′ (where each R′ is independently selected        from hydrogen, lower alkyl, C₃-C₇ cycloalkyl, heterocyclyl,        heteroaryl, —OH, or NH₂), —S(O)R″ (where R″ is lower alkyl, or        cycloalkyl), —S(O)₂R′″ (where R′″ is lower alkyl, or        cycloalkyl), or any two adjacent R_(1a) together form        heterocycyl or heteroaryl.    -   l) R₂ is methyl, R₃ is hydrogen, and R₄ is selected from        heteroaryl or aryl each of which may be independently        substituted by one to three substituents selected from halogen        (in particular; Cl, Br or F), C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl (in particular —CF₃), C₁₋₆        haloalkoxy (such as —OCF₃), —OH, phenyl, benzyl, phenoxy,        benzyloxy, benzoyl, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, —CN,        —S(O)₂NH₂, —S(O)₂NHC₁₋₄ alkyl, —S(O)₂N(C₁₋₄ alkyl)₂, C₁₋₆        alkylcarbonyl, C₁₋₆ alkoxycarbonyl, —S(O)R′″ (where R′″ is lower        alkyl or cycloalkyl) and —S(O)₂R′″ (where R′″ is lower alkyl, or        cycloalkyl), and m is 1 or 2, and each R_(1a) is independently        selected from the group consisting of optionally substituted        lower alkyl, optionally substituted aryl, optionally substituted        aryloxy, optionally substituted heteroaryl, optionally        substituted heterocyclyl, —P═O(OH)(NH₂), —C(O)NR′R′,        —NR′S(O)₂NR′R′, —NR′—S(O)₂R′, —NR′C(O)R′, —S(O)₂—NR′R′ and        —NR′R′ (where each R′ is independently selected from hydrogen,        lower alkyl, C₃-C₇ cycloalkyl, heterocyclyl, heteroaryl, —OH, or        NH₂), —S(O)R″ (where R″ is lower alkyl, or cycloalkyl),        —S(O)₂R′″ (where R′″ is lower alkyl, or cycloalkyl), or any two        adjacent R_(1a) together form heterocyclyl or heteroaryl.    -   m) R₂ and R₃ together form a C₄-C₉ cycloalkyl ring, preferably        cyclopentyl or cyclohexyl ring, and R₄ is selected from        heteroaryl or aryl each of which may be independently        substituted by one to three substituents selected from halogen        (in particular, Cl, Br or F), C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl (in particular —CF₃), C₁₋₆        haloalkoxy (such as —OCF₃), —OH, phenyl, benzyl, phenoxy,        benzyloxy, benzoyl, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, —CN,        —S(O)₂NH₂, —S(O)₂NHC₁₋₄ alkyl, —S(O)₂N(C₁₋₄ alkyl)₂, C₁₋₆        alkylcarbonyl, C₁₋₆ alkoxycarbonyl, —S(O)R′″ (where R′″ is lower        alkyl or cycloalkyl) and —S(O)₂R′″ (where R′″ is lower alkyl, or        cycloalkyl), and m is 1 or 2, and each R_(1a) is independently        selected from the group consisting of optionally substituted        lower alkyl, optionally substituted aryl, optionally substituted        aryloxy, optionally substituted heteroaryl, optionally        substituted heterocyclyl, —P═O(OH)(NH₂), —C(O)NR′R′,        —NR′S(O)₂NR′R′, —NR′—S(O)₂R′, —NR′C(O)R′, —S(O)₂—NR′R′ and        —NR′R′ (where each R′ is independently selected from hydrogen,        lower alkyl, C₃-C₇ cycloalkyl, heterocyclyl, heteroaryl, —OH, or        NH₂), —S(O)R″ (where R″ is lower alkyl, or cycloalkyl),        —S(O)₂R′″ (where R′″ is lower alkyl, or cycloalkyl), or any two        adjacent R_(1a) together form heterocyclyl or heteroaryl.

In relation to the aforementioned compounds the following furtherdefinitions may apply:

-   -   n) R₂ and R₃ together form a cyclohexyl or cyclopentyl ring.    -   o) R₂ and R₃ together form a cyclohexyl or cyclopentyl ring, and        R₄ is selected from heteroaryl or aryl each of which may be        Independently substituted by one to three substituents selected        from halogen (in particular, Cl, Br or F), C₁₋₆ alkyl, C₁₋₆        alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl (in        particular —CF₃), C₁₋₆ haloalkoxy (such as —OCF₃), —OH, phenyl,        benzyl, phenoxy, benzyloxy, benzoyl, —NHC₁₋₄ alkyl, —N(C₁₋₄        alkyl)₂, —CN, —S(O)₂NH₂, —S(O)₂NHC₁₋₄ alkyl, —S(O)₂N(C₁₋₄        alkyl)₂, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, —S(O)R′″        (where R′″ is lower alkyl or cycloalkyl) and —S(O)₂R′″ (where        R′″ is lower alkyl, or cycloalkyl).    -   p)R₂ and R₃ together form a cyclohexyl or cyclopentyl ring, and        R₄ is selected from heteroaryl or aryl each of which may be        independently substituted by one to three substituents selected        from halogen (in particular, Cl, Br or F), C₁₋₆ alkyl, C₁₋₆        alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl (in        particular —CF₃), C₁₋₆ haloalkoxy (such as —OCF₃), —OH, phenyl,        benzyl, phenoxy, benzyloxy, benzoyl, —NHC₁₋₄ alkyl, —N(C₁₋₄        alkyl)₂, —CN, —S(O)₂NH₂, —S(O)₂NHC₁₋₄ alkyl, —S(O)₂N(C₁₋₄        alkyl)₂, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, and sulfone        (in particular —S(O)₂C₁₋₄ alkyl), and m is 1 or 2, and each        R_(1a) is independently selected from the group consisting of        optionally substituted lower alkyl, optionally substituted aryl,        optionally substituted aryloxy, optionally substituted        heteroaryl, optionally substituted heterocyclyl, —P═O(OH)(NH₂),        —C(O)NR′R′, NR′S(O)₂NR′R′, —NR′—S(O)₂R′, —NR′C(O)R′,        —S(O)₂—NR′R′ and —NR′R′ (where each R′ is independently selected        from hydrogen, lower alkyl, C₃-C₇ cycloalkyl, heterocyclyl,        heteroaryl, —OH, or NH₂), —S(O)R″ (where R″ is lower alkyl, or        cycloalkyl), —S(O)₂R′″ (where R′″ is lower alkyl, or        cycloalkyl), or any two adjacent R_(1a) together form        heterocyclyl or heteroaryl;

In relation to the aforementioned compounds one or more of the followingpreferred definitions (where appropriate) may also apply:

-   -   q) each R_(1a) is independently selected from the group        consisting of optionally substituted lower alkyl, optionally        substituted aryl, optionally substituted aryloxy, optionally        substituted heteroaryl, optionally substituted heterocyclyl,        —P═O(OH)(NH₂), —C(O)NR′R′, —NR′S(O)₂NR′R′, —NR′—S(O)₂R′,        —NR′C(O)R′, —S(O)₂—NR′R′ and —NR′R′ (where each R′ is        independently selected from hydrogen, lower alkyl, C₃-C₇        cycloalkyl, heterocyclyl, heteroaryl, —OH, or NH₂), —S(O)R″        (where R″ is lower alkyl, or cycloalkyl), —S(O)₂R′″ (where R′″        is lower alkyl, or cycloalkyl), or any two adjacent R_(1a)        together form    -   r) m is 1.

In a further embodiment and with reference to all of the aforementionedcompounds R₅ is H or CH₃.

In a further embodiment and with reference to all of the aforementionedformulae, the following additional preferred definitions may also apply.

R₄ is selected from:

wherein Hal is a halogen;

-   -   p is 0, 1 or 2; and    -   each R₉ is independently selected from halogen, CN, NO₂,        haloalkyl, aryl, heteroaryl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, C₁₋₃        alkyl, or CO₂R′ (where R′ is a lower alkyl or H);        or

wherein Hal is a halogen;

-   -   p is 0, 1 or 2; and    -   each R₉ is independently selected from halogen, CN, NO₂,        haloalkyl, aryl, heteroaryl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, C₁₋₃        alkyl, or CO₂R′ (where R′ is a lower alkyl or H);        or

-   (c) a heteroaryl substituted from 1 to 3 times from a group selected    from C₁-C₃ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆    haloalkyl, C₁₋₃ haloalkoxy, —OH, phenyl, benzyl, phenoxy, benzyloxy,    benzoyl, —NH₂, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, —CN, mercapto, C₁₋₆    alkylcarbonyl, C₁₋₆ alkoxycarbonyl, CO₂H, —S(O)R′″ (where R′″ is    lower alkyl or cycloalkyl) and —S(O)₂R′″ (where R′″ is lower alkyl,    cycloalkyl or OH).    -   In an embodiment R₄ is selected from pyridyl, pyrazolyl or        thiazolyl.

In yet a further embodiment and with reference to the compounds of theinvention of formulae (I) and (Ib):

-   -   R₁ is phenyl independently substituted by one or two        substituents selected from independently selected from the group        consisting of optionally substituted lower alkyl, optionally        substituted aryl (preferably optionally substituted phenyl),        optionally substituted aryloxy (preferably optionally        substituted phenyloxy), optionally substituted heteroaryl,        optionally substituted heterocyclyl, —P═O(OH)(NH₂), —C(O)NR′R′,        —NR′S(O)₂NR′R′, —NR′—S(O)₂R′, —NR′C(O)R′, —S(O)₂—NR′R′ and        —NR′R′ (where each R′ is independently selected from hydrogen,        lower alkyl, C₃-C₇ cycloalkyl, heterocyclyl, heteroaryl, —OH, or        NH₂), —S(O)R″ (where R″ is lower alkyl, or cycloalkyl),        —S(O)₂R′″ (where R′″ is lower alkyl, cycloalkyl), or any two        adjacent substituents together form heterocyclyl or heteroaryl;    -   R₂ and R₃ are the same and represent C₁₋₄ alkyl, or together a        C₅-C₆ cycloalkyl;    -   R₄ is heteroaryl or heteroaryl independently substituted one or        two times by    -   C₁₋₄ alkyl, C₁₋₄ haloalkyl, halogen, or C₁₋₄ alkoxy; or is        phenyl or phenyl independently substituted one or two times by        C₁₋₄ alkyl, C₁₋₄ haloalkyl, halogen, or C₁₋₄ alkoxy; and    -   R₅ is H or lower alkyl.

In a further embodiment and with reference to any one of formula (I),(Ia), (Ib), (Ic) or (Ia′), n is 1-3, for instance, n=1, n=2, or n=3.Preferably n=1.

In an embodiment m is 1 and R_(1a) is selected from:

-   -   —S(O)₂R′″ (where R″ is lower alkyl, or cycloalkyl),    -   —S(O)₂NR′R″ (where R′ is hydrogen and R″ is selected from        hydrogen, lower alkyl, —OH, or NH₂),    -   lower alkyl, substituted 1 or 2 times with a substituent group        selected from CF₃ and NH₂,    -   lower haloalkyl,    -   optionally substituted heterocyclyl (preferably 4 or 5-membered        heterocyclyl),    -   —NR′S(O)₂NR′R′ (where each R′ is independently selected from        hydrogen or lower alkyl, C₃-C₇ cycloalkyl, heterocyclyl, or        heteroaryl), or    -   —NR′—S(O)₂R′ (where each R′ is independently selected from        hydrogen or lower alkyl, C₃-C₇ cycloalkyl, heterocyclyl, or        heteroaryl).

In a further embodiment the R_(1a) substituent is in the para position.

In an embodiment m is 1 and R_(1a) is selected from

In an embodiment m is 1 and the substituent is in the para position.

In a further preferred embodiment and with reference to any one offormula (I), (Ia), (Ib), (Ic), or (Ia′), n is 1 and R₁ or

In an embodiment R_(1a) is

In an embodiment R_(1a) is

In the list below (which are representative examples of compounds of thepresent invention) the structures contain one or more stereogeniccenters, the respective structures are depicted without absoluteconfiguration. These structures also include pure stereoisomers in eachpossible absolute configuration as well as mixtures of isomers in allratios including racemates.

The salts of the compounds of the invention are preferablypharmaceutically acceptable, but it will be appreciated thatnon-pharmaceutically acceptable salts also fall within the scope of thepresent invention, since these are useful as intermediates in thepreparation of pharmaceutically acceptable salts.

It will be appreciated that the compounds of the invention, and thesalts thereof, can be presented in the form of pharmaceuticallyacceptable derivatives. The term “pharmaceutically acceptablederivative” includes pharmaceutically acceptable esters, prodrugs,solvates and hydrates of the compounds of the invention, or saltsthereof. Pharmaceutically acceptable derivatives may include anypharmaceutically acceptable hydrate or any other compound or prodrugwhich, upon administration to a subject, is capable of providing(directly or indirectly) a compound of the invention, or an activemetabolite or residue thereof.

The pharmaceutically acceptable salts include acid addition salts, baseaddition salts, and the salts of quaternary amines and pyridiniums. Theacid addition salts are formed from a compound of the invention and apharmaceutically acceptable inorganic or organic acid including but notlimited to hydrochloric, hydrobromic, sulfuric, phosphoric,methanesulfonic, toluenesulphonic, benzenesulphonic, acetic, propionic,ascorbic, citric, malonic, fumaric, maleic, lactic, salicylic, sulfamic,or tartaric acids. The counter ion of quaternary amines and pyridiniumsinclude chloride, bromide, iodide, sulfate, phosphate, methansulfonate,citrate, acetate, malonate, fumarate, sulfamate, and tartrate. The baseaddition salts include but are not limited to salts such as sodium,potassium, calcium, lithium, magnesium, ammonium and alkylammonium.Also, basic nitrogen-containing groups may be quaternised with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchlorides, bromides and iodides; dialkyl sulfates like dimethyl anddiethyl sulfate; and others. The salts may be made in a known manner,for example by treating the compound with an appropriate acid or base inthe presence of a suitable solvent.

The compounds of the invention may be in crystalline form and/or assolvates (e.g. hydrates) and it is intended that both forms be withinthe scope of the present invention. The term “solvate” is a complex ofvariable stoichiometry formed by a solute (in this invention, a compoundof the invention) and a solvent. Such solvents should not interfere withthe biological activity of the solute. Solvents may be, by way ofexample, water, ethanol or acetic acid. Methods of solvation aregenerally known within the art.

The term “pro-drug” is used in its broadest sense and encompasses thosederivatives that are converted in vivo to the compounds of theinvention. Such derivatives would readily occur to those skilled in theart, and include, for example, compounds where a free hydroxy group isconverted into an ester derivative or a ring nitrogen atom is convertedto an N-oxide. Examples of ester derivatives include alkyl esters,phosphate esters, and those formed from amino acids, preferably valine.Any compound that is a prodrug of a compound of the invention is withinthe scope and spirit of the invention.

The term “pharmaceutically acceptable ester” includes biologicallyacceptable esters of compound of the invention such as sulphonic,phosphonic and carboxylic acid derivatives.

Thus, in another aspect of the invention, there is provided a prodrug orpharmaceutically acceptable ester of a compound of the invention or ofsalt thereof.

It will be appreciated that the compounds of the invention have at leastone asymmetric centre, and therefore are capable of existing in morethan one stereoisomeric form. The invention extends to each of theseforms Individually and to mixtures thereof, including racemates. Theisomers may be separated conventionally by chromatographic methods orusing a resolving agent. Alternatively the individual isomers may beprepared by asymmetric synthesis using chiral intermediates. Where thecompound has at least one carbon-carbon double bond, it may occur in Z-and E-forms with all isomeric forms of the compounds being included inthe present invention.

It will be appreciated that in respect of the cyclopropyl carbons whichconnect variables R₆ and R₁ that these chiral positions give rise tovarious stereoisomers. In an embodiment the invention contemplatestrans-isomers. In another embodiment the invention contemplatescis-isomers. In a further embodiment the invention contemplates anenantiomeric mixture of trans-isomers. In a further embodiment theinvention provides a single trans-enantiomer, or an enantiomericallyenriched mixture thereof.

The invention also includes where possible a salt or pharmaceuticallyacceptable derivative such as a pharmaceutically acceptable ester,solvate and/or prodrug of the above mentioned embodiments of theinvention.

In another aspect of the invention, there is provided a pharmaceuticalcomposition that comprises a therapeutically effective amount of one ormore of the aforementioned compounds or pharmaceutically acceptablesalts thereof, including pharmaceutically acceptable derivativesthereof, and optionally a pharmaceutically acceptable carrier ordiluent.

In another aspect, the present invention provides pharmaceuticalcompositions for use as a positive allosteric modulator of α7nAChRs, forinstance in the treatment or prevention of cognitive deficits associatedwith neurodegeneration or neuropsychiatric diseases, or in treatinginflammation or in treating neuropathic pain, the composition comprisingan effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof, including a pharmaceuticallyacceptable derivative thereof, and optionally a pharmaceuticallyacceptable carrier or diluent.

Accordingly these compositions may be thought as either procognitive orantiinflammatory or neuroprotective agents or analgesics.

The term “composition” is intended to include the formulation of anactive ingredient with encapsulating material as carrier, to give acapsule in which the active ingredient (with or without other carrier)is surrounded by carriers.

The pharmaceutical compositions or formulations include those suitablefor oral, rectal, nasal, topical (including buccal and sub-lingual),vaginal or parenteral (including intramuscular, sub-cutaneous andintravenous) administration or in a form suitable for administration byinhalation or insufflation.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalcompositions and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, or capsules filled with thesame, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use.

Such pharmaceutical compositions and unit dosage forms thereof maycomprise conventional ingredients in conventional proportions, with orwithout additional active compounds or principles, and such unit dosageforms may contain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed.Formulations containing ten (10) milligrams of active ingredient or,more broadly, 0.1 to one hundred (100) milligrams, per tablet, areaccordingly suitable representative unit dosage forms.

The compounds of the present invention can be administered in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispensable granules. Asolid carrier can be one or, more substances which may also act asdiluents, flavouring agents, solubilisers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid that is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

Sterile liquid form compositions include sterile solutions, suspensions,emulsions, syrups and elixirs. The active ingredient can be dissolved orsuspended in a pharmaceutically acceptable carrier, such as sterilewater, sterile organic solvent or a mixture of both.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and may contain formulation agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in, powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, eg. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilisers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilising agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavoured base, usually sucroseand acacia or tragacanth; pastilles comprising the active ingredient inan inert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multidose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomising spray pump. To improve nasal delivery andretention the compounds according to the invention may be encapsulatedwith cyclodextrins, or formulated with other agents expected to enhancedelivery and retention in the nasal mucosa.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 5 to 10 microns or less.Such a particle size may be obtained by means known in the art, forexample by micronisation.

When desired, formulations adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The invention also includes the compounds in the absence of carrierwhere the compounds are in unit dosage form.

The amount of the compound of the invention to be administered may be inthe range from about 10 mg to 2000 mg per day, depending on the activityof the compound and the disease to be treated.

Liquids or powders for intranasal administration, tablets or capsulesfor oral administration and liquids for intravenous administration arethe preferred compositions.

The pharmaceutical preparations of the compounds according to thepresent invention may be co-administered with one or more other activeagents in combination therapy. For example the pharmaceuticalpreparation of the active compound may be co-administered (for example,separately, concurrently or sequentially), with one or more other agentsused to treat cognitive impairment or mood disorders such asacetylcholine esterase inhibitors, antipsychotics, and antidepressants.

It is believed that the compounds of the invention may be beneficial intreating patients with cognitive impairment or aid in increasingcognition. It is believed that this effect may be brought about bypositive allosteric modulation of α7 nAChRs. Positive allostericmodulators (PAMs) of nicotinic acetylcholine receptors (nAChRs) can becharacterised by two types (type I and type II). Whilst both potentiatepeak agonist-induced responses, they have different effects on the rateof agonist-induced receptor desensitization. Type I PAMs have little orno effect on the rapid rate of desensitization that is characteristicsof α7 nAChRs, whereas type II PAMs cause dramatic slowing of receptordesensitization.

In one embodiment the compounds of formula (I), (Ia), (Ib) or (Ic) (andsubformulae thereof) are characterised as type I.

In one embodiment the compounds of formula (I), (Ia), (Ib) or (Ic) (andsubformulae thereof) are characterised as type II.

It is envisaged that the compounds may additionally be useful in thetreatment of patients, including a mammal and especially a human,suffering from neuropsychiatric diseases and neurodegenerative diseasesinvolving a dysfunction of the cholinergic system, and furtherconditions of memory and/or cognitive impairment, including, forexample, schizophrenia, Attention Deficit Hyperactivity Disorder,anxiety, mania, depression, manic depression (as examples ofneuropsychiatric disorders), Tourette's syndrome, Parkinson's disease,Huntington's disease (as examples of neurodegenerative diseases), and/orcognitive disorders (such as Alzheimer's disease, Lewy Body Dementia,Amyotrophic Lateral Sclerosis, memory impairment, memory loss, cognitiondeficit).

Neurodegenerative disorders include, but are not limited to, treatmentand/or prophylaxis of Alzheimer's diseases, Pick's disease, diffuse LewyBody disease, progressive supranuclear palsy (or Steel-Richardsonsyndrome), multisystem degeneration (or Shy-Drager syndrome), motorneuron diseases including amyotrophic lateral sclerosis, degenerativeataxias, cortical basal degeneration, ALS-Parkinson's-Dementia complexof Guam, subacute sclerosing panencephalitis, Huntington's disease,Parkinson's disease, synucleinopathies, primary progressive aphasia,striatonigral degeneration, Machado-Joseph disease/spinocerebellarataxia type 3, olivopontocerebellar degenerations, Gilles De LaTourette's disease, bulbar, pseudobulbar palsy, spinal muscular atrophy,spinobulbar muscular atrophy (Kennedy's disease), primary lateralsclerosis, familial spastic paraplegia, Werdnig-Hoffmann disease,Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease,familial spastic disease, Wohlfart-Kugelberg-Welander disease, spasticparaparesis, progressive multifocal leukoencephalopathy, prion diseases(such as Creutzfeldt-Jakob, Gerstmann-Straussler-Scheinker disease, Kuruand fatal familial insomnia), and neurodegenerative disorders resultingfrom cerebral ischemia or infarction including embolic occlusion andthrombotic occlusion as well as intracranial hemorrhage of any type(including, but not limited to, epidural, subdural, subarachnoid andintracerebral), and intracranial and intravertebral lesions (including,but not limited to, contusion, penetration, shear, compression andlaceration).

In addition, the compounds of the invention may be used to treatage-related dementia and other dementias and conditions with memory lossincluding age-related memory loss, senility, vascular dementia, diffusewhite matter disease (Binswanger's disease), dementia of endocrine ormetabolic origin, dementia of head trauma and diffuse brain damage,dementia pugilistica and frontal lobe dementia.

The invention provides methods of treating subjects suffering frommemory impairment due to, for example, Alzheimer's disease, mildcognitive impairment due to aging, schizophrenia, Attention DeficitHyperactivity Disorder, Parkinson's disease, multiple sclerosis,Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease,depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility,multiinfarct dementia and other neurological conditions, as well as HIVand cardiovascular diseases.

For certain of the abovementioned conditions it is clear that thecompounds may be used prophylactically as well as for the alleviation ofsymptoms. References herein to “treatment” or the like are to beunderstood to include such prophylactic treatment, as well astherapeutic treatments.

The compounds of the present invention as agents which modulate the α7nAChR may be particularly useful in the therapeutic or prophylactictreatment of diseases such as schizophrenia, bi-polar disorder, anxiety,AD, ADHD, mild cognitive impairment, Parkinson's Disease, Huntington'sdisease, Tourette's syndrome, brain trauma, jetlag and nicotineaddiction.

Accordingly in a further aspect of the invention, there is provided ameans for ameliorating the cognitive deficits associated withneurodegenerative and neuropsychiatric diseases and also inflammatorydiseases by the application of a positive allosteric modulators of α7nAChRs selected from a compound of the invention, or salt thereof,including a pharmaceutically acceptable derivative thereof, or acomposition comprising the compound of the invention, or salt thereof,or a pharmaceutically acceptable derivative thereof.

In another aspect of the invention a method is provided for preventingor treating cognitive deficits involving dysfunction of the cholinergicsystem including the step of administrating a compound of the invention,or salt thereof, or a composition comprising the compound or saltthereof.

In another preferred form of the invention there is provided a methodfor preventing or treating neurodegenerative or neuropsychiatricdisorders including the step of administrating a compound of theinvention, or a pharmaceutically acceptable salt thereof, including apharmaceutically acceptable derivative thereof, or a compositioncomprising the compound or pharmaceutically acceptable salt thereof, orpharmaceutically acceptable derivative thereof.

In a further aspect of the present invention, there is provided the useof a compound of the invention, or salt thereof, in the preparation of amedicament for the treatment (therapeutic or prophylactic) of diseasestates in which modulation of α7 nAChRs would be beneficial.

In a further aspect of the invention there is provided a process for theproduction of the compounds of the invention, or salts thereof,including pharmaceutically acceptable derivatives thereof.

Compounds of the invention may be prepared according to the followinggeneral schemes:

Compounds of the formula (I) can be prepared by synthetic procedures asdepicted in Scheme A. Cinnamate esters 1 may be from commercial sourcesor prepared by Doebner modification of Knoevenagel condensation of anaryl/heteroaryl aldehyde. Typically, an aryl/heteroaryl aldehyde 1 andester of malonic acid 2 is heated in pyridine/piperidine mixture.Numerous modifications of this procedure as well as alternatives such asAldol-type condensation or Wittig reaction of aryl or heteroarylcarbonyl compounds with ylides are possible and will be readily apparentto those skilled in the art.

Cyclopropanation of olefin was carried out by reacting cinnamate ester 3with phosphorus ylides derived from phosphonium salts 4 (where X═Cl, Br,I) as described in J. Med. Chem. 2001, 44, 3302. The requisitephosphonium salts can be purchased or prepared by known methods. Thoseskilled in the art will understand that cyclopropanation of olefinscould be achieved by alternative methods, such as Simmons-Smith typereaction of cinnamate ester with Furukawa reagents as described inTetrahedron 1969, 25, 2647 or Michael initiated ring closing reaction ofcinnamate ester with sulphur ylides as described in Synthesis 2008, 20,3279. Additionally, treatment of olefins with diazoesters in thepresence of metal catalysts can afford access to cyclopropane esters oftype 5 with either cis or trans orientation of R¹ to the ester moietyfavoured depending on catalyst used (Tetrahedron 2008, 7041). Ester 5where R₂ and R₃ are chloro can be, prepared by heating a mixture ofcinnamate ester 3 and ethyl trichlorooacetate. Numerous modifications ofthis procedure such as use of trichioroacetic acid in acetic anhydrideas described in J. Org. Chem. 1988, 53, 4945 are possible and will bereadily apparent to those skilled in the art. Similarly, ester 5 whereR₂ and R₃ are fluoro can be prepared by heating cinnamate 3 with adifluoro carbene generated from suitable reagent such as trimethylsilylfluorosulfonyldifluoroacetate as described in J: Fluorine Chem. 2004,125, 459. Esters 6 where R₂ and R₃ together form a cycloalkyl orcycloalkenyl group can be prepared by from corresponding Spiro groupcontaining phosphorus ylides. Alternatively, phosphorus ylides where R²and R³ contains terminal alkene group can be reacted with cinnamateesters, followed by ring-closure metathesis as described in J, Chem.Res. 2006, 9, 591 to form ester 5 where R₂ and R₃ together formcycloalkenyl group, which could be further reduced to form correspondingcycloalkyl group containing ester 5. Ester 5 can be alternativelyprepared by the reaction of styrenes with diazoesters givingcyclopropanes in high enantiomeric and diastereomeric excess usingchiral ligands and metal catalysts as outlined in J. Am. Chem. Soc.1991, 726.

Ester 5 can be hydrolysed to acid 6 by using known procedures and thenreacted with thionyl chloride or oxalyl chloride to offer acid chloride,which can be then reacted with amine 7 to offer amides 8. Numerousalternative amide formation procedures could be used such as directcoupling of acid with amine in presence of dicyclohexyldiimide or otherdiimides, O-(7-azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HATU), propylphosphonic anhydride (T3P) or conversionof acid to reactive anhydride and then coupling with amine to generateamides 8.

Amides 8 can be reduced by use of borane tetrahydrofuran complex togenerate compounds of formula (I). Other reagents such as lithiumaluminium hydride or sodium metal in 1-propanol could be used to effectthis transformation.

Scheme B outlines the synthesis of compounds of formula (I) from esters5 (where R¹=Ph). Ester 5 can be hydrolysed to acid 6 by using knownprocedures and then reacted with amine 7 to offer amides 8 as outlinedabove. Amide 8 can be converted to sulfonyl chloride through treatmentwith chlorosulfonic acid and subsequently allowed to react with amine 10to generate sulfonamides 11. Amides 11 can be reduced by use of boranetetrahydrofuran complex or other aforementioned reagents to providecompounds of formula (I).

Scheme C describes an alternative route to compounds of formula (I).Ester 5 can be reduced to alcohol 12 using standard procedures;alternatively alcohol 12 can be prepared with high enantiomeric excessform from cinnamyl alcohols using Furukawa type chemistry and chiralligands (J. Am. Chem. Soc. 1994, 2651, Tetrahedron Letters 1992, 2575).Oxidation of alcohol 12 to give aldehyde 13 can be achieved usingstandard oxidative methods such as Swern Oxidation, PCC or MnO₂.Reductive amination of aldehyde 13 can be achieved using standardprocedures to give amines 14. Sulfonamidation of amine 14 via sulfonylchloride to yield compounds of formula (I) can be achieved as describedabove.

Scheme D describes potential synthesis of compounds of formula (I) wheren=2. Aldehyde 13 can be homologated by reaction withmethoxymethyl-triphenylphosphonium chloride to form the enol etherfollowed by acid catalysed deprotection and tautomerisation to aldehyde16 (J. Org. Chem, 2008, 5163). Aldehyde 16 can then conceivably betransformed to compounds of formula (I) as described for aldehyde 13above. Alternatively, acid 6 can be homologated by employingArndt-Eistert homologation/amidation chemistry (Org. Biomol. Chem.,2006, 323) and the subsequent amide 19 could be transformed intocompounds of formula (I) by procedures outlined above for amide 8.

Scheme E outlines another route to the synthesis of compounds of formula(I) from ester 5 (where R¹=Ph). Ester 5 can be converted to sulfonylchloride 22, through treatment with chlorosulfonic acid, andsubsequently allowed to react with amine 10 to generate sulfonamides 23.Ester 23 may be reduced using standard conditions to give alcohol 24,followed by oxidation using standard conditions to give aldehyde 25.Reductive amination with aldehyde 25 and amine 7, can be achieved usingstandard procedures to provide compounds of formula (I) as indicatedabove.

Scheme F outlines another route to the synthesis of compounds of formula(I) from ester 5 (where R¹=4-BrPh). Ester 5 can be reduced to alcohol 26using standard procedures such as LiAlH₄ in refluxing THF. Alternativelyalcohol 26 can be prepared with high enantiomeric excess form fromcinnamyl alcohols using Furukawa type chemistry and chiral ligands (J.Am. Chem. Soc. 1994, 2651, Tetrahedron Letters 1992, 2575). Oxidation ofalcohol 26 to give aldehyde 27 can be achieved using standard oxidativemethods such as Swern Oxidation, PCC or MnO₂. Reductive amination ofaldehyde 27 can be achieved using standard procedures to give amines 28.A variety of conditions for palladium mediated couplings can be used tocouple 28 with, for example a boronic acid substrate or amine substrateto give compounds of formula (I). Sulfonamides 32 are also suitablesubstrates for palladium mediated couplings. To those skilled in the artit will be apparent that a range of metal catalysed couplings can beaffected on this substrate to give an extensive range of substituents atR⁶ and R¹².

Alternatively, ester 5 can be hydrolysed to acid 29 by using knownprocedures and then reacted with amine 7 to offer amides 30 usingaforementioned reagents and techniques. A variety of conditions forpalladium mediated couplings can be used to couple 30 with, for examplea boronic acid substrate or amine substrate to give amides 31 or 33 viareaction with sulphonamides 32. Amides 31 and 33 can be reduced by useof borane tetrahydrofuran complex or other aforementioned reagents toprovide compounds of formula (I).

Scheme G outlines another route to the synthesis of compounds of formula(I) from commercially available ester 34. Ester 34 can be hydrolysed toacid 35 by using known procedures and then reacted with amine 7 to offeramides 36 using aforementioned reagents and techniques. Amide 36 can beconverted to sulfonyl chloride 37, through treatment with chlorosulfonicacid, and subsequently allowed to react with amine 10 to generatesulfonamides 38. Amides 38 can be reduced by use of boranetetrahydrofuran complex or other afore mentioned reagents to providecompounds of formula (I).

Another variation is to add, remove or modify the substituents of theproduct to form new derivatives. This could be achieved again by usingstandard techniques for functional group inter-conversion, well known inthe industry such as those described in Comprehensive OrganicTransformations: A Guide to Functional Group Preparations by Larock R C,New York, VCH Publishers, Inc. 1989.

Examples of possible functional group inter-conversions are: —C(O)NRR′from —CO₂CH₃ by heating with or without catalytic metal cyanide, e.g.NaCN, and HNRR′ in CH₃OH; —OC(O)R from —OH with e.g., ClC(O)R′ Inpyridine; —NR—C(S)NR′R″ from —NHR with an alkylisothiocyanate orthiocyanic acid; —NRC(O)OR from —NHR with alkyl chloroformate;—NRC(O)NR′R″ from —NHR by treatment with an isocyanate, e.g. HN═C═O orRN═C═O; —NRC(O)R′ from —NHR by treatment with ClC(O)R′ in pyridine;—C(═NR)NR′R″ from —C(NR′R″)SR′″ with H₃NR*OAc by heating in alcohol;—C(NR′R″)SR from —C(S)NR′R″ with R—I in an inert solvent, e.g. acetone;—C(S)NR′R″ (where R′ or R″ is not hydrogen) from —C(S)NH₂ with HNR′R″;—C(═NCN)—NR′R″ from —C(═NR′R″)—SR with NH₂CN by heating in anhydrousalcohol, alternatively from —C(═NH)—NR′R″ by treatment with BrCN andNaOEt in EtOH; —NR—C(═NCN)SR from —NHR′ by treatment with (RS)₂C═NCN;—NR″SO₂R from —NHR′ by treatment with ClSO₂R by heating in pyridine;—NR′C(S)R from —NR′C(O)R by treatment with Lawesson's reagent[2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide];—NRSO₂C F₃ from —NHR with triflic anhydride and base, —CH(NH₂)CHO from—CH(NH₂)C(O)OR′ with Na(Hg) and HCl/EtOH; —CH₂C(O)OH from —C(O)OH bytreatment with SOCl₂ then CH₂N₂ then H₂O/Ag₂O; —C(O)OH from —CH₂C(O)OCH₃by treatment with PhMgX/HX then acetic anhydride then CrO₃; R—OC(O)R′from RC(O)R′ by R″CO₃H; —CCH₂OH from —C(O)OR′ with Na/R′OH; —CHCH₂ from—CH₂CH₂OH by the Chugaev reaction; —NH₂ from —C(O)OH by the Curtiusreaction; —NH₂ from —C(O)NHOH with TsCl/base then H₂O; —CHC(O)CHR from—CHCHOHCHR by using the Dess-Martin Periodinane regent orCrO₃/aqH₂SO₄/acetone; —C₆H₅CHO from —C₆H₅CH₃ with CrO₂Cl₂; —CHO from —CNwith SnCl₂/HCl; —CN from —C(O)NHR with PCl₅; —CH₂R from —C(O)R withN₂H₄/KOH; —S(O)₂R from —SR with mCPBA.

In order that the present invention may be more readily understood, weprovide the following non-limiting examples.

EXAMPLES Synthetic Procedure

All anhydrous solvents were commercially obtained and stored inSure-Seal bottles under nitrogen. All other reagents and solvents werepurchased as the highest grade available and used without furtherpurification. Thin-layer chromatography (TLC) analysis of reactionmixtures was performed using Merck silica gel 60 F254 TLC plates andvisualized using ultraviolet light. Silica gel 60 (40-63 μm, Merck) wasused for flash chromatography. Melting points were measured using anElectrothermal 1002 apparatus and were uncorrected. ¹H NMR (300 MHz) and¹³C NMR (75 MHz) spectra were obtained on a Bruker Advance 300 NMRspectrometer using residual signal of deuterated NMR solvent as internalreference. Mass spectral data and purity of all compounds were acquiredon an Agilent LCMS-Ion Trap-1200 Series. Mass spectra were obtained onan Agilent Ion Trap applying electrospray ionization (ESI). Purity ofall compounds was obtained using a Nucleodur 3 μm 4.6×150 mmreverse-phase column. The eluent was a linear gradient with a flow rateof 1.3 mL/min from 95% A and 5% B to 5% A and 95% B in 8.5 min (solventA, H₂O with 0.1% HCO₂H; solvent B, acetonitrile with 0.1% HCO₂H). Thecompounds were detected at their maximum of absorbance.

In the examples below, in case the structures contain one or morestereogenic centres, the respective structure is depicted in anarbitrary absolute configuration. These structures depict singleenantiomers as well as mixtures of enantiomers in all ratios, and/ormixtures of diastereoisomers in all ratios.

General Procedures General Procedure A: Aldol Condensation toα,β-Unsaturated Esters

A solution of the aldehyde (1.0 equiv.) and monoethyl malonate (1.3equiv.) in anhydrous pyridine (5 equiv.) containing piperidine (0.1equiv.) was refluxed for 12 h under an argon atmosphere. The reactionmixture was cooled to room temperature, quenched with 2N HCl, andextracted with ether. The extracts were washed with water, saturatedNaHCO₃, and brine. The organic solution was dried over Na₂SO₄ andconcentrated in vacuo. The crude mixture was purified by columnchromatography (SiO₂, cyclohexane/CH₂Cl₂) to furnish the pureα,β-unsaturated ester.

General Procedure B: Cyclopropanation of α,β-Unsaturated Esters

To a suspension of the alkylphosphonium halide (1.2 equiv.) in anhydrousTHF (0.3 M) at −78° C. was added n-BuLi (2.0 M in cyclohexane, 1.1equiv.) under an argon atmosphere. The resulting mixture was warmed to0° C. and stirred for 30 min. The reaction mixture was cooled to −78° C.followed by the addition of a solution of the α,β-unsaturated ester (1.0equiv.) in anhydrous THF (0.5 M). The reaction mixture was stirred for 2h at 0° C., then slowly warmed to ambient temperature and stirredovernight. The solution was poured onto 1N HCl. The aqueous layer wasextracted with ethyl acetate and the combined organic layers weresequentially washed with saturated NaHCO₃, brine, dried over Na₂SO₄, andconcentrated in vacuo. The crude cyclopropane was purified by columnchromatography (SiO₂, cyclohexane/CH₂Cl₂) to furnish the purecyclopropyl ester.

General Procedure C: Saponification of Esters

To the ester (1.0 equiv.) in a solution of THF: water (1:4) (0.4 M), wasadded NaOH (1.1 equiv.). The mixture was stirred overnight at 60° C.followed by removal of the volatiles in vacuo. The remaining aqueoussolution was acidified with 1N HCl and then twice extracted with ethylacetate. The organic extracts were combined and washed with brine, driedover Na₂SO₄ and concentrated in vacuo to furnish the pure carboxylicacid.

General Procedure D: Amide Bond Formation Through Acid Chloride (ThionylChloride Derived) Intermediates

To the carboxylic acid (1.0 equiv.) was added thionyl chloride (10.0equiv.) at 0° C. and 2 drops of anhydrous DMF under an argon atmosphere.The mixture was stirred for 2 h at room temperature before the mixturewas concentrated in vacuo. Co-evaporation with toluene, in vacuo, wasused to remove the remaining thionyl chloride. The crude acid chloridewas dissolved in anhydrous DCM under an argon atmosphere, cooled to 0°C. and Et₃N (5.0 equiv.) was added followed by the addition ofaniline/amine (1.0 equiv.). The mixture was stirred for 16 h at ambienttemperature, after this time reaction mixture was concentrated in vacuoand the crude residue directly purified by column chromatography (SO₂,cyclohexane/ethyl acetate) to furnish the pure amide.

General Procedure E: Formation of Sulfonamides

Chlorosulfonic acid (5-16 equiv.) was added drop-wise at 0° C. to asolution of the arene (1.0 equiv.) in chloroform (0.5 M) under an argonatmosphere. The reaction mixture was stirred at rt until completeconversion to sulfonyl chloride was achieved, then poured into aice/brine mixture. The phases were separated and the aqueous layerextracted with Et₂O twice. The combined organic extracts were dried overNa₂SO₄, and concentrated in vacuo. The crude sulfonyl chloride wasdissolved in a 0.5 M solution of amine in 1,4-dioxane (10.0 equiv.),stirred at ambient temperature for 45 min and evaporated to drynessunder vacuum. The crude sulfonamide was purified by columnchromatography (SiO₂, cyclohexane/ethyl acetate then EtOAc/MeOH) ortriturated with EtOAc/MeOH to give the pure sulfonamide.

General Procedure F: Reduction of Amides to Amines

To the amide (1.0 equiv.), as a solution in anhydrous THF (0.5 M) at 0°C. under an argon atmosphere was added, drop-wise, a 1M solution of BH₃in THF (3.0-6.0 equiv.). The mixture was stirred for 1 h at roomtemperature and then 3 h at reflux. The reaction mixture was cooled to0° C. and HCl 1N (5.0 equiv.) was added carefully. The mixture was thenstirred at reflux for 1 h. After cooling to ambient temperature, themixture was neutralized with NaOH 1N and extracted with ethyl acetate.The combined organic phases were dried (MgSO₄), filtered andconcentrated in vacuo. The crude residue was purified by columnchromatography (SiO₂, cyclohexane/ethylacetate) to furnish the desiredamine.

General Procedure G: Reduction of Esters to Alcohols

The ester (1 equiv.) was suspended in anhydrous Et₂O (0.1 M) under a N₂atmosphere and was cooled to 0° C. LiAlH₄ (2 equiv.) was added in oneportion and the mixture was allowed to stir at 0° C. for 20 minutesbefore warming to ambient temperature. Once the reaction was deemed tobe complete by LCMS analysis the reaction mixture was cooled to 0° C.and potassium sodium tartrate tetrahydrate 1.0 M solution (˜30 ml) wasadded slowly. The mixture was left to stir at ambient temperature for 1h before neutralisation with 2 M aq. HCl solution. The mixture wasextracted with EtOAc (×4) and the organic extracts were washed withbrine (×2) before being dried over MgSO₄ and concentrated in vacuo. Thecrude residue was purified by column chromatography (SiO₂,cyclohexane/CH₂Cl₂) to furnish the desired alcohol.

General Procedure H: Oxidation of Alcohols to Aldehydes Using PCC

A solution of alcohol (1.0 equiv.) in anhydrous dichloromethane (0.2 M)under an argon atmosphere was rapidly added to a slurry of pyridiniumchlorochromate (1.5 equiv.) in anhydrous dichloromethane (0.3 M) andthis mixture was stirred at ambient temperature for 2 h. Diethyl etherwas added and the mixture was passed through Celite, eluting withdiethyl ether. The filtrate was concentrated in vacuo and the cruderesidue was purified by column chromatography (SiO₂, cyclohexane/CH₂Cl₂)to furnish the desired aldehyde.

General Procedure I: Reductive Amination of Aldehydes

To amine (1.0 equiv.) and aldehyde (1.0 equiv.) in anhydrousdichloromethane (0.12 M) under an argon atmosphere, was added acatalytic amount of acetic acid. The mixture was stirred at ambienttemperature for 12 h before addition of NaBH(OAc)₄ (2.0 equiv.). Thereaction mixture was stirred at ambient temperature for 2 h, thesolution was then concentrated in vacuo and the crude residue waspurified by column chromatography (SIO₂, cyclohexane/CH₂Cl₂) to furnishthe desired amine.

General Procedure J: Amide Bond Formation Through Acid Chloride (Derivedfrom Oxalyl Chloride) Intermediates

To a solution of the acid (1 equiv.) in anhydrous dichloromethane (0.4M) under an atmosphere of N₂ at 0° C., was added DMF (cat.). A solutionof oxalyl chloride in anhydrous dichloromethane (1.28 M) was addeddrop-wise. The reaction mixture was stirred for 1 h at 0° C. beforewarming to RT and stirring for a further 1 h. The dichloromethane wasremoved in vacuo or by evaporation under a steady flow of N₂. The crudematerial was taken up in anhydrous Et₂O (0.4 M), under an atmosphere ofN₂, and cooled to 0° C. A solution of amine (1.05 equiv.) and NEt₃ (1equiv.) in anhydrous Et₂O (0.47 M amine) was added drop-wise. Uponcompletion of the reaction as determined by LCMS analysis (30 min.-1 h)the reaction was quenched by addition of H₂O and the product wasextracted into EtOAc (3×), dried (MgSO₄ or Na₂SO₄) and concentrated invacuo. The crude residue could be used as is or purified by columnchromatography (SiO₂, EtOAc/hexane) to give the desired amide

Intermediate A: ±transN-(5-chloro-2-methoxyphenyl)-2-phenylcyclopropanecarboxamide

2-phenylcyclopropanecarboxylic acid (200 mg, 1.23 mmol) and5-chloro-2-methoxyaniline (194 mg, 1.23 mmol) were reacted as describedunder General Procedure D to furnish the title compound (328 mg, 88%) asa white solid. ESIMS m/z [M+H]⁺302.3.

Intermediate B: ±transN-(5-chloro-2-methoxyphenyl)-2-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate A (323 mg, 1.09 mmol) and ammonia (excess) were, reacted asdescribed under General Procedure E to furnish the title compound (244mg, 60%) as a white solid. ESIMS m/z [M+H]⁺381.0.

Intermediate C: ±transN-(4-fluorophenyl)-2-phenylcyclopropanecarboxamide

2-phenylcyclopropanecarboxylic acid (200 mg, 1.23 mmol) and4-fluoroaniline (144 mg, 1.30 mmol) were reacted as described underGeneral Procedure D to furnish the title compound (297 mg, 94%) as awhite solid. ESIMS m/z [M+H]⁺256.2.

Intermediate D: ±transN-(4-fluorophenyl)-2-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate C (281 mg, 1.10 mmol) and ammonia (excess) were reacted asdescribed under General Procedure E to furnish the title compound whichwas used crude in subsequent synthetic steps. ESIMS m/z [M+H]⁺ 335.2.

Intermediate E: ±transN-(3,4-difluorophenyl)-2-phenylcyclopropanecarboxamide

2-phenylcyclopropanecarboxylic acid (200 mg, 1.23 mmol) and3,4-difluoroaniline (167 mg, 1.30 mmol) were reacted as described underGeneral Procedure D to furnish the title compound (291 mg, 86%) as awhite solid. ESIMS m/z [M+H]⁺274.2.

Intermediate F: ±transN-(3,4-difluorophenyl)-2-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate E (279 mg, 1.02 mmol) and ammonia (excess) were reacted asdescribed under General Procedure E to furnish the title compound whichwas used crude in subsequent synthetic steps. ESIMS m/z [M+H]⁺353.0.

Intermediate G: ±trans ethyl2,2-dimethyl-3-phenylcyclopropanecarboxylate

Isopropyltriphenylphosphonium iodide (21.6 g, 50 mmol) and ethylcinnamate (8.81 g, 50 mmol) were reacted as described under GeneralProcedure B to furnish the title compound (6.58 g, 60%) as a colorlessoil. ESIMS m/z [M+H]⁺219.3.

Intermediate H: ±trans 2,2-dimethyl-3-phenylcyclopropanecarboxylic acid

Intermediate G (6.58 g, 30.1 mmol) was reacted as described underGeneral Procedure C to furnish the title compound (5.15 g, 90%) as awhite solid. ESIMS m/z [M−H]⁻189.2.

Intermediate I: ±transN-(5-chloro-2-methoxyphenyl)-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate H (1.00 g, 5.3 mmol) and 5-chloro-2-methoxyaniline (1.00 g,6.3 mmol) were reacted as described under General Procedure D to furnishthe title compound (1.02 g, 59%) as a white solid. Mp 155-157° C. ESIMSm/z [M+H]⁺ 330.1.

Intermediate J: ±transN-(5-chloro-2-methoxyphenyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate I (430 mg, 1.30 mmol) was reacted as described underGeneral Procedure E to give the title compound (357 mg, 67%) as a whitesolid. Mp 129-133° C. ESIMS m/z [M+H]⁺409.1.

Intermediate K: ±trans 2,2-dimethyl-N,3-diphenylcyclopropanecarboxamide

Intermediate H (500 mg, 2.6 mmol) and aniline (294 mg, 3.2 mmol) werereacted as described under General Procedure D to give the titlecompound (655 mg, 94%) as a white solid. Mp 143-145° C. ESIMS m/z[M+H]⁺266.2.

Intermediate L: ±trans2,2-dimethyl-N-phenyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate K (655 mg, 2.5 mmol) was reacted as described under GeneralProcedure E to give the title compound (270 mg, 32%) as a white solid.ESIMS m/z [M+H]⁺ 345.2.

Intermediate M: ±transN,2,2-trimethyl-N,3-diphenylcyclopropanecarboxamide

Intermediate H (500 mg, 2.6 mmol) and N-methyl aniline (338 mg, 3.2mmol) were reacted as described under General Procedure D to give thetitle compound (712 mg, 97%) as a yellow solid. Mp 59-61° C. ESIMS m/z[M+H]⁺ 280.2.

Intermediate N: ±transN,2,2-trimethyl-N-phenyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate M (700 mg, 2.5 mmol) reacted as described under GeneralProcedure E to give the title compound (400 mg, 44%) as a white solid.ESIMS m/z [M+H]⁺359.2.

Intermediate O: ±transN-(5-chloro-2-methoxyphenyl)-N,2,2-trimethyl-3-phenylcyclopropanecarboxamide

To a stirred suspension of sodium hydride (60% suspension in mineraloil, 175 mg, 4.4 mmol) in dry DMF (10 ml) at 0° C., under an argonatmosphere was added Intermediate I (960 mg, 2.9 mmol). The solution wasthen stirred at ambient temperature for 20 minutes at which pointiodomethane (0.72 ml, 11.6 mmol) was slowly added at 0° C. and thereaction mixture stirred at ambient temperature for 12 h. Solvent wasthen removed in vacuo and the crude oil was purified by columnchromatography (SiO₂, cyclohexane/AcOEt 100:0→80:20) to give the titlecompound (964 mg, 96%) as a yellow oil. Compound appears as rotationalisomers in a 1:1 ratio, ESIMS m/z [M+H]⁺344.2.

Intermediate P: ±transN-(5-chloro-2-methoxyphenyl)-N,2,2-trimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate O (749 mg, 2.2 mmol) reacted as described under GeneralProcedure E to give the title compound (230 mg, 25%) as a white solid.ESIMS m/z [M+H]⁺423.2.

Intermediate Q: ±trans ethyl 2-phenylspiro[2.4]heptane-1-carboxylate

Cyclopentyltriphenylphosphonium bromide (10.3 g, 25 mmol) and ethylcinnamate (4.40 g, 25 mmol) were reacted as described under GeneralProcedure B to furnish the title compound (3.72 g, 61%) as a colorlessoil. ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.11 (m, 5H), 4.22-4.13 (m, 2H),2.77 (d, 1H), 2.15 (d, 1H), 1.91-1.85 (m, 2H), 1.72-1.27 (m, 9H).

Intermediate R: ±trans 2-phenylspiro[2.4]heptane-1-carboxylic acid

Intermediate Q (3.72 g, 15.2 mmol) was reacted as described underGeneral Procedure C to furnish the title compound (3.19 g, 96%) as awhite solid. ¹H NMR (300 MHz, CDCl₃) δ 7.33-7.11 (m, 5H), 2.83 (d, 1H),2.17 (d, 1H), 1.97-1.32 (m, 8H).

Intermediate S: ±transN-(5-chloro-2-methoxyphenyl)-2-phenylspiro[2,4]heptane-1-carboxamide

Intermediate R (400 mg, 1.85 mmol) and 5-chloro-2-methoxyaniline (291mg, 1.85 mmol) were reacted as described under General Procedure D tofurnish the title compound (560 mg, 85%) as a beige solid. Mp 133-135°C. ESIMS m/z [M+H]⁺356.2.

Intermediate T: ±transN-(5-chloro-2-methoxyphenyl)-2-(4-sulfamoylphenyl)spiro[2.4]heptane-1-carboxamide

Intermediate S (200 mg, 0.56 mmol) was reacted as described underGeneral Procedure E to give the title compound (140 mg, 58%) as a whitesolid. Mp 210-212° C. ESIMS m/z [M+H]⁺435.2.

Intermediate U: ±transN-(2,6-dimethoxypyridin-3-yl)-2-phenylspiro[2.4]heptane-1-carboxamide

Intermediate Q (300 mg, 1.39 mmol) and 2,6-dimethoxy-pyridin-3-ylamine(214 mg, 1.39 mmol) were reacted as described under General Procedure Dto furnish the title compound (260 mg, 52%) as a purple solid. Mp131-133° C. ESIMS m/z [M+H]⁺353.2.

Intermediate V; transN-(2,6-dimethoxypyridin-3-yl)-2-(4-sulfamoylphenyl)spiro[2,]heptane-1-carboxamide

Intermediate U (170 mg, 0.47 mmol) was reacted as described underGeneral Procedure E to give the title compound (105 mg, 63%) as a whitesolid. Mp 112-115° C. ESIMS m/z [M+H]⁺432.3.

Intermediate W: ±trans (2,2-dimethyl-3-phenylcyclopropyl)methanol

Intermediate G (2.18 g, 10 mmol) was reacted as described under GeneralProcedure G to furnish the title compound (1.56 g, 88%) as a colourlessoil. ¹H NMR (300 MHz, CDCl₃) δ 7.30-7.24 (m, 3H), 7.20-7.15 (m, 21-f),3.90 (dd, 1H), 3.71 (dd, 1H), 1.76 (d, 1H), 1.44 (td, 1H), 1.39 (s, 1H),1.30 (s, 3H), 0.86 (s, 3H).

Intermediate X: ±trans 2,2-dimethyl-3-phenylcyclopropanecarbaldehyde

Intermediate W (1.0 g, 5.7 mmol) was reacted as described under GeneralProcedure H to furnish the title compound (765 mg, 76%) as a colourlessoil. ¹H NMR (300 MHz, CDCl₃) δ 9.58 (d, 1H), 7.33-7.22 (m, 3H),7.19-7.13 (m, 2H), 2.95 (d, 1H), 2.18 (t, 1H), 1.45 (s, 3H), 0.98 (s,3H).

Intermediate Y: t transN-(5-fluoropyridin-3-yl)-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate H (0.200 g, 1.05 mmol) and 3-amino-5-fluoropyridine (0.124g, 1.10 mmol) were reacted as described under General Procedure J tofurnish the title compound (287 mg, 96%) which was used crude in thenext step. ESIMS m/z [M+H]⁺285.2.

Intermediate Z: ±transN-(5-fluoropyridin-3-yl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate Y (285 mg) was reacted as described under General ProcedureE to furnish the title compound (385 mg) which was used crude in thenext step. ESIMS m/z [M+H]⁺364.0.

Intermediate AA: ±trans2,2-dimethyl-3-phenyl-N-[2-(trifluoromethyl)pyridin-4-yl]cyclopropanecarboxamide

Intermediate H (203 mg, 1.07 mmol) and4-amino-2-(trifluoromethyl)pyridine (182 mg, 1.12 mmol) were reacted asdescribed under General Proceudur J to furnish the title compound (375mg) which was used crude in the next step. ESIMS m/z [M+H]⁺335.2.

Intermediate AB: ±trans2,2-dimethyl-3-(4-sulfamoylphenyl)-N-[2-(trifluoromethyl)pyridin-4-yl]cyclopropanecarboxamide

Intermediate M (375 mg) was reacted as described under General ProcedureE to furnish the title compound (423 mg) which was used crude in thenext step. ESIMS m/z [M+H]⁺414.0.

Intermediate AC: ±trans2-phenyl-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopropanecarboxamide

2-Phenylcyclopropanecarboxylic acid (48 mg, 0.30 mmol) and2-amino-5-(trifluoromethyl)pyridine (51 mg, 0.31 mmol) were reacted asdescribed under General Procedure J to furnish the title compound (48mg, with a major impurity still present) after purification by pTLC (50%DCM/hexane). Compound was used crude in the next step. ESIMS m/z[M+H]⁺307.3.

Intermediate AD: ±trans2-(4-sulfamoylphenyl)-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopropanecarboxamide

Intermediate AC (48 mg, 0.16 mmol) was reacted as described underGeneral Procedure E to furnish the title compound (51 mg) which was usedcrude in the next step. ESIMS m/z [M+H]⁺386.0.

Intermediate AE: ±transN-(4-fluorophenyl)-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate H (201 mg, 1.06 mmol) and 4-fluoroaniline (123 mg, 1.11mmol) were reacted as described under General Procedure J to furnish thetitle compound (265 mg) which was used crude in the next step. ESIMS m/z[M+H]⁺284.2.

Intermediate AF: ±transN-(4-fluorophenyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate AE (265 mg) was reacted as described under GeneralProcedure E to furnish the title compound which was used crude in thenext step. ESIMS m/z [M+H]⁺363.3.

Intermediate AG: ±transN-(3,4-difluorophenyl)-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate H (201 mg, 1.06 mmol) and 3,4-difluoroaniline (143 mg, 1.11mmol) were reacted as described under General Procedure J to furnish thetitle compound (270 mg) which was used crude in the next step. ESIMS m/z[M+H]⁺302.3.

Intermediate AH: ±transN-(3,4-difluorophenyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate AG (270 mg) was reacted as described under GeneralProcedure E to furnish the title compound which was used crude in thenext step. ESIMS m/z [M+H]⁺381.0.

Intermediate AI and Intermediate AJ:(4S)-4-benzyl-3-{[(1S,2S)-2-phenylcyclopropyl]carbonyl}-1,3-oxazolidin-2-oneand(4S)-4-benzyl-3-{[(1,2R)-2-phenylcyclopropyl]carbonyl}-1,3-oxazolidin-2-one

A solution of 2-phenylcyclopropanecarboxylic acid (3.80 g, 23.4 mmol) inanhydrous DCM (40 ml), under an atmosphere of N₂, was cooled to 0° C.and DMF (cat.) added. A solution of oxalylchloride (8.92 g, 70.3 mmol)in anhydrous DCM (36 ml) was added drop-wise via a cannula. The solutionwas stirred at 0° C. for 45 minutes before warming to ambienttemperature and stirring for 1 h. The solution was concentrated in vacuoand then taken up in anhydrous THF (35 ml). Meanwhile, a solution of(S)-4-benzyl-2-oxazolidinone (4.29 g, 23.4 mmol) in anhydrous THF (35ml), under N₂, was cooled to −78° C. A solution of nBuLi in cyclohexane(1.9 M, 12.3 ml, 23.4 mmol) was added drop-wise and stirred for 30minutes at −78° C. A solution of the crude acid chloride, preparedabove, in anhydrous THF, was added via a cannula and the reactionmixture allowed to slowly attain ambient temperature overnight. Thefollowing morning the reaction was quenched by addition of NH₄Cl (sat.aq.) and further diluted with H₂O. The product was then extracted withEtOAc (2×) and dichloromethane (2×). The pooled organic extracts weredried (MgSO₄), filtered and concentrated in vacuo. The isomers wereseparated via a combination of column chromatography (40%EtOAc/petroleum ether) and fractional crystallisation (first elutingisomer—40% EtOAc/hexane, second eluting isomer—dichloromethane/heptane),yielding Intermediate AI as a white crystalline solid (1.9 g, 50%) andIntermediate AJ as a white crystalline solid (1.4 g, 37%).

Intermediate AI (first eluting): ¹H NMR (300 MHz, CDCl₃) δ 7.38-7.15 (m,10H), 4.70 (dq, 1H), 4.24-4.16 (m, 2H), 3.60-3.54 (m, 1H), 3.32 (dd,),2.80 (dd, 1H), 2.73-2.66 (m, 1H), 1.81 (dq, 1H), 1.53-1.47 (m, 1H).ESIMS m/z [M+H]⁺322.3.

Intermediate AJ (second eluting): ¹H NMR (300 MHz, CDCl₃) δ 7.35-7.19(m, 10H), 4.76-4.68 (m, 1H), 4.26-4.15 (m, 2H), 3.61-3.55 (m, 1H), 3.30(dd, J=13.5 Hz, 3.3 Hz, 1H), 2.80 (dd, J 13.5, 9.6 Hz, 1H), 2.75-2.70(m, 1H), 1.77 (dq,), 1.55-1.42 (m, 1H). ESIMS m/z [M+H]⁺322.3.

Note: stereochemistry was assigned to each isomer retrospectivelyfollowing comparison of optical rotation of Intermediates AK and AL toliterature values.

Intermediate AK: (1S,2S)-2-phenylcyclopropanecarboxylic acid

A THF:H₂O mixture (3:1 v/v, 40 ml) was added to Intermediate AI (1.88 g,5.85 mmol) and the mixture allowed to stir for a few minutes to allowalmost complete dissolution, before cooling to 0° C. Hydrogen peroxide(35%, 4.5 ml, 46.8 mmol) was added, followed by lithium hydroxide (0.56g, 23.4 mmol). The reaction mixture was stirred at 0° C. for 30 minutesbefore warming to ambient temperature and stirring for 1.5 h. Thereaction mixture was then cooled to 0° C. and 1.5 M sodium sulphitesolution (46.8 mmol) was added and the reaction mixture stirred at 0° C.for 15 minutes before warming to ambient temperature and stirring foranother 15 minutes. The aqueous phase was extracted with Et₂O (3×) andthen acidified to pH 1 with conc. HCl. The solution was then extractedwith Et₂O (4×), and the combined organic extracts dried (MgSO4),filtered and concentrated in vacuo to give Intermediate AK (900 mg, 95%)as a clear viscous oil. ¹HNMR (300 MHz, CDCl₃) δ 7.35-7.09 (m, 5H), 2.61(ddd, 1H), 1.91 (dq, J=4.8, 3.9, 1H), 1.67 (q, 1H), 1.42 (dq, 1H). ESIMSm/z [M−H]⁺161.2. [α]^(24.5)+249.261 (c 0.102, MeOH). Absolutestereochemistry assigned by comparison with literature (JMC 2000, p3923; JMC 2011, p 957).

Intermediate AL: (1R,2R)-2-phenylcyclopropanecarboxylic acid

Intermediate AJ (1.40 g, 4.37 mmol) was reacted according to theprocedure described for Intermediate AK, to yield the title compoundwith a minor impurity (837 mg) which was used without furtherpurification. ¹HNMR (300 MHz, CDCl₃) δ¹HNMR (300 MHz, CDCl₃) δ 7.35-7.09(m, 5H), 261 (ddd, 1H), 1.91 (dq, 1H), 1.67 (q, 1H), 1.42 (dq, 1H).ESIMS m/z [M−H]⁺161.2. [α]_(D) ^(24A)-259.546 (c 0.119, MeOH). Absolutestereochemistry assigned by comparison with literature (JMC 2000, p3923; JMC 2011, p 957).

Intermediate AM and Intermediate AN(4S)-4-benzyl-3-{[(1R,3R)-2,2-dimethyl-3-phenylcyclopropyl]carbonyl}-1,3-oxazolidin-2-oneand(4S)-4-benzyl-3-{([(1S,3S)-2,2-dimethyl-3-phenylcyclopropyl]carbonyl}-1,3-oxazolidin-2-one

Intermediate H (1.167 g, 6.13 mmol) was reacted according to theprocedure described for Intermediates AI and AJ. The isomes wereseparated via a combination of column chromatography (1:2:7,Et₂O/Hexane/Toluene) and fractional crystallisation of the first elutingisomer only (heptane) (71% overall yield):

Intermediate AM (first eluting): ¹H NMR (300 MHz, CDCl₃) δ 7.38-7.19 (m,10H), 4.68-4.76 (m, 1H), 4.26-4.16 (m, 2H), 3.38-3.32 (m, 2H), 2.95 (d1H), 2.77 (dd, 1H), 1.39 (s, 3H), 1.06 (s, 3H). ESIMS m/z [M−H]⁺350.3.Analysis of this isomer by x-ray crystallography enabled absolutestereochemical assignment of Intermediates AM and AN.

Intermediate AN (second eluting): ¹H NMR (300 MHz, CDCl₃) δ 7.37-7.17(m, 10H), 4.81-4.73 (m, 1H), 4.27-4.17 (m, 2H), 3.42 (d, 1H), 3.34 (dd,1H), 2.95 (d, 1H), 2.83 (dd, 1H), 1.35 (s, 3H), 1.02 (s, 3H). ESIMS m/z[M−H]⁺350.3.

Intermediate AO: (R,R)-2,2-dimethyl-3-phenylcyclopropanecarboxylic acid

Intermediate AM (1.44 g, 4.11 mmol) was reacted according to theprocedure described for Intermediate AK, to yield the title compound(707 mg), which was used without further purification. ESIMS m/z[M−H]⁺189.2.

Intermediate AP: (S,S)-2,2-dimethyl-3-phenylcyclopropanecarboxylic acid

Intermediate AN (450 mg, 1.29 mmol) was reacted according to theprocedure described for Intermediate AK, to yield the title compound(187 mg), which was used without further purification, ESIMS m/z[M−H]⁺189.2.

Alternatively, Intermediate H was separated into constituent enantiomers(Intermediate AO and AP) using SFC (Lux C4, CO₂/Methanol 17:3, 3mLmin-1, 35° C., 100 bar), Intermediate AO was the first eluting isomerRt=2.36 min, 100% ee, [α]_(D) ^(25.0)+27.725° ee, (MeOH, c=1.020), andIntermediate AP the second eluting isomer, Rt=3.01 min, 98.17% ee,[α]_(D) ^(26.1)-27.800° (MeOH, c=1.000). Stereochemistry was confirmedby reacting the second eluting acid (Rt=3.01 min), according to theprocedure outlined for Intermediates AI and AJ, to give Intermediate ANwhich was matched by ¹H NMR.

Intermediate AQ:(1R,3R)—N-[4-fluoro-2-(trifluoromethyl)phenyl]-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate AO (259 mg, 1.36 mmol) and 2-amino-5-fluorobenzotrifluoride(264 mg, 1.43 mmol) was reacted as described under General Procedure Jto furnish the title compound (423 mg) as an off white solid which wasused without further purification in the next step. ESIMS m/z[M+H]⁺352.3.

Intermediate AR:(1R,3R)—N-[4-fluoro-2-(trifluoromethyl)phenyl]-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate AQ (413 mg, 1.18 mmol) was reacted as described underGeneral Procedure E to furnish the title compound (382 mg) which wasused without further purification in the next step. ESIMS m/z[M+H]⁺431.0.

Intermediate AS:(1R,3R)—N-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate AO (237 mg, 1.25 mmol) and5-fluoro-2-(2,2,2-trifluoroethoxy)aniline HCl (321 mg, 1.3 mmol) werereacted as described under General Procedure J (except 2 equiv. of NEt₃were used) to furnish the title compound (437 mg) of a pale brown oil,which was used without further purification in the next step. ESIMS m/z[M+H]⁺382.0.

Intermediate AT:(1R,3R)—N-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate AS (427 mg, 1.12 mmol) was reacted as described underGeneral Procedure E to furnish the title compound (435 mg) which wasused without further purification in the next step. ESIMS m/z[M−H]⁺459.2.

Intermediate AU:(1S,3S)—N-[4-fluoro-2-(trifluoromethyl)phenyl]-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate AP (184 mg, 0.969 mmol) and2-amino-5-fluorobenzotrifluoride (182 mg, 1.02 mmol) were reacted asdescribed under General Procedure J to furnish the title compound (336mg) as a pale yellow gum which was used without further purification inthe next step. ESIMS m/z [M+H]⁺352.3.

Intermediate AV:(1S,3S)—N-[4-fluoro-2-(trifluoromethyl)phenyl]-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate AU (331 mg, 0.942 mmol) was reacted as described underGeneral Procedure E to furnish the title compound (308 mg) as a whitecrystalline solid which was used without further purification in thenext step. ESIMS m/z [M+H]⁺431.0.

Intermediate AW:(1R,2R)—N-(4-fluorophenyl)-2-phenylcyclopropanecarboxamide

Intermediate AL (200 mg, 1.23 mmol) and 4-fluoroaniline (144 mg, 1.30mmol) were reacted as described under General Procedure J to furnish thetitle compound which was used without further purification in the nextstep. ESIMS m/z [M+H]⁺256.2.

Intermediate AX:(1R,2R)—N-(4-fluorophenyl)-2-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate AW (300 mg, 1.18 mmol) was reacted as described underGeneral Procedure E to furnish the title compound which was used withoutfurther purification in the next step. ESIMS m/z [M−H]⁺333.3.

Intermediate AY:(1R,2R)-2-phenyl-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopropanecarboxamide

Intermediate AL (250 mg, 1.54 mmol) and2-amino-5-(trifluoromethyl)pyridine (262 mg, 1.62 mmol) were reacted asdescribed under General Procedure J to furnish the title compound (145mg, 31%) after purification by column chromatography (15-20%EtOAc/hexane, 3 columns). ESIMS m/z [M−H]⁺307.3.

Intermediate AZ:(1R,2R)-2-(4-sulfamoylphenyl)-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopropanecarboxamide

Intermediate AY (140 mg, 0.45 mmol) was reacted as described underGeneral Procedure E to furnish the title compound which was used withoutfurther purification in the next step. ESIMS m/z [M+H]⁺386.0.

Intermediate BA:(1R,3R)—N-(5-chloro-2-methoxyphenyl)-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate AO (275 mg, 1.45 mmol) and 5-chloro-2-methoxyaniline (239mg, 1.52 mmol) were reacted as described under General Procedure J tofurnish the crude title compound (466 mg) as a colourless oil, which wasused without further purification. ESIMS m/z [M+H]⁺330.1.

Intermediate BB:(1R,3R)—N-(5-chloro-2-methoxyphenyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate BA (466 mg) was reacted as described under GeneralProcedure E to give the crude title compound (540 mg) as a whitecrystalline solid which was used without further purification. ESIMS m/z[M+H]⁺409.1.

Intermediate BC:(1S,3S)—N-(5-chloro-2-methoxyphenyl)-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate AP (200 mg, 1.05 mmol) and 5-chloro-2-methoxyaniline (174mg, 1.1 mmol) were reacted as described under General Procedure J tofurnish the crude title compound (347 mg) as an off white crystallinesolid, which was used without further purification. ESIMS m/z[M+H]⁺3301.

Intermediate BD:(1R,3R)—N-(5-chloro-2-methoxyphenyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate BC (347 mg) was reacted as described under GeneralProcedure E to give the title compound (349 mg) as white crystallinesolid which was used without further purification. ESIMS m/z[M+H]⁺409.1.

Intermediate BE: ±transN-(5-chloro-2-methylphenyl)-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate H (400 mg, 2.10 mmol) and 5-chloro-2-methylaniline (357 mg,2.50 mmol) were reacted as described under General Procedure D tofurnish the title compound which was purified by column chromatography(cyclohexane→60% DCM/cyclohexane) to give the title compound as a whitesolid (486 mg, 73%). ¹H NMR (300 MHz, CDCl₃) δ 8.01 (br s, 1H),7.32-7.03 (m, 8H), 2.85 (d, 1H), 2.28 (s, 3H), 1.86-1.85 (m, 1H), 1.43(s, 3H), 0.98 (s, 3H).

Intermediate BF: ±transN-(5-chloro-2-methylphenyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate BE (486 mg, 1.5 mmol) was reacted as described underGeneral Procedure E to furnish the title compound which was purified bycolumn chromatography (230 mg, 49%) as a white solid. ESIMS m/z[M+H]⁺393.2.

Intermediate BG: ±transN-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate H (400 mg, 2.10 mmol) and 5-fluoro-2-methoxyaniline (356mg, 2.50 mmol) were reacted as described under General Procedure D tofurnish the title compound which was purified by column chromatography(cyclohexane→60% DCM/cyclohexane) to give the title compound, as ayellow solid (459 mg), which contained an amount of the3-fluoro-6-methoxyaniline starting material. The compound was used as isin the next step without further purification. ESIMS m/z [M+H]⁺314.2.

Intermediate BH: ±transN-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate BG (459 mg, 1.47 mmol) was reacted as described underGeneral Procedure E to furnish the title compound which was purified bycolumn chromatography (230 mg, 42%) as a white solid. ESIMS m/z[MH]⁺393.2.

Intermediate BI: ±transN-(3-chlorophenyl)-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate H (375 mg, 1.97 mmol) and 3-chloroaniline (503 mg, 3.94mmol) were reacted as described under General Procedure D to furnish thetitle compound which was purified by column chromatography (440 mg, 74%)as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.69 (br s, 1H), 7.46 (br s,1H), 7.40-7.33 (m, 1H), 7.32-7.17 (m, 6H), 7.11-7.04 (m, 1H), 2.84 (d,1H), 1.83 (d, 1H), 1.41 (s, 3H), 0.97 (s, 3H).

Intermediate BJ: ±transN-(3-chlorophenyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate BI (440 mg, 1.46 mmol) was reacted as described underGeneral Procedure E to furnish the title compound which was purified bycolumn chromatography (350 mg, 71%) as a white solid. ESIMS m/z[M+H]⁺379.2.

Intermediate BK: ±trans2,2-dimethyl-N-[3-morpholin-4-yl)phenyl]-3-phenylcyclopropanecarboxamide

intermediate H (300 mg, 1.58 mmol) and 3-morpholin-4-ylaniline (338 mg,1.89 mmol) were reacted as described under General Procedure D. Thecrude material was purified by column chromatography (cyclohexane→1:1EtOAc/cyclohexane) to give the title compound (412 mg, 74%). ESIMS m/z[M−H]⁺351.3.

Intermediate BL: ±trans2,2-dimethyl-N-[3-(morpholin-4-yl)phenyl]-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate BK (412 mg, 1.18 mmol) was reacted as described underGeneral Procedure E to furnish the title compound which was purified bycolumn chromatography (cyclohexane→20% EtOAc/cyclohexane) to give awhite solid (294 mg, 58%). ESIMS [M+H]⁺430.2.

Intermediate BM: ±transN-(5-chloro-2-ethoxyphenyl)-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate H (300 mg, 1.58 mmol) and 5-chloro-2-ethoxyaniline (325 mg,1.89 mmol) were reacted as described under General Procedure D. Thecrude material was purified by column chromatography (cyclohexane 40%EtOAc/cyclohexane) to give the title compound (357 mg, 68%) as a yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ 8.51 (br s, 1H), 7.97 (br s, 1H),7.33-7.19 (m, 5H), 6.97 (dd, 1H), 6.78 (d, 1H), 4.13 (q, 2H), 2.84 (d,1H), 1.85 (d, 1H), 1.50 (t, 3H), 1.43 (s, 3H), 1.00 (s, 3H).

Intermediate BN: ±transN-(5-chloro-2-ethoxyphenyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate BM (166 mg, 1.36 mmol) was reacted as described underGeneral Procedure E to furnish the title compound which was purified bycolumn chromatography (cyclohexane 50% EtOAc/cyclohexane) to give awhite solid (345 mg, 60%). ESIMS m/z [M+H]⁺423.1.

Intermediate BO: ±transN-[2-methoxy-5-(triluoromethyl)phenyl]-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate H (400 mg, 2.1 mmol) and2-methoxy-5-(trifluoromethyl)aniline (488 mg, 2.59 mmol) were reacted asdescribed under General Procedure D. The crude material was purified bycolumn chromatography (cyclohexane→60% DCM/cyclohexane) to give thetitle compound, as a yellow solid (713 mg), contaminated with the excess2-methoxy-5-trifluoromethylaniline starting material. This compound wasused as is in the next step. ¹H NMR (300 MHz, CDCl₃) δ 8.79 (s, 1H),8.03 (s, 1H), 7.33-7.11 (m, 6H), 6.94 (d, 1H), 3.98 (s, 3H), 2.86 (d,1H), 1.89 (d, 1H), 1.43 (s, 3H), 1.00 (s, 3H).

Intermediate BP: ±transN-[2-methoxy-5-(trifluoromethyl)phenyl]-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate BO (713 mg, 1.9 mmol) was reacted as described underGeneral Procedure E to furnish the title compound which was purified bycolumn chromatography to give a white solid (230 mg, 35%). ESIMS m/z[M+H]⁺443.2.

Intermediate BQ:(1R,3R)—N-(5-fluoro-2-methylphenyl)-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate AO (150 mg, 0.79 mmol) and 5-fluoro-2-methylaniline (188mg, 0.94 mmol) were reacted as described under General Procedure D. Thecrude material was purified by column chromatography to yield thedesired product as a white solid (160 mg, 68%). ¹H NMR (300 MHz, CDCl₃)δ 7.84 (br s, 1H), 7.32-7.09 (m, 7H), 6.79-6.71 (m, 1H), 2.85 (d, 1H),2.27 (s, 3H), 1.87 (d, 1H), 1.42 (s, 3H), 0.98 (s, 3H).

Intermediate BR:(1R,3R)—N-(5-fluoro-2-methylphenyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate BQ (160 mg, 0.53 mmol) was reacted as described underGeneral Procedure E to furnish the title compound which was purified bycolumn chromatography to give a white solid (130 mg, 66%). ESIMS m/z[M+H]⁺377.2.

Intermediate BS:(1R,3R)—N-(4,5-difluoro-2-methylphenyl)-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate AO (150 mg, 0.79 mmol) and 4,5-difluoro-2-methylaniline(115 mg, 0.79 mmol) were reacted as described under. General ProcedureD. The crude material was purified by column chromatography to yield thedesired product as a white solid (230 mg, 93%). ¹H NMR (300 MHz, CDCl₃)δ 7.84-7.78 (m, 1H), 7.32-7.17 (m, 6H), 7.01-6.95 (m, 1H), 2.83 (d, 1H),2.25 (s, 3H), 1.86 (d, 1H), 1.41 (s, 3H), 0.98 (s, 3H),17

IntermediateBT:(1R,3R)—N-(4,5-difluoro-2-methylphenyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate BS (260 mg, 0.82 mmol) was reacted as described underGeneral Procedure E to give the title compound (242 mg, 74%) as a whitesolid. Mp 209-212° C. ESIMS m/z [M+H]⁺395.2.

Intermediate BU:(1S,3S)—N-(5-fluoro-2-methylphenyl)-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate AP (180 mg, 0.94 mmol) and 5-fluoro-2-methylaniline (188mg, 0.94 mmol) were reacted as described under General Procedure D. Thecrude material was purified by column chromatography to yield thedesired product as a white solid (250 mg, 90%). ¹H NMR (300 MHz, CDCl₃)δ 7.87 (br s, 1H), 7.32-7.10 (m, 7H), 6.80-6.72 (m, 1H), 2.85 (d, 1H),2.28 (s, 3H), 1.85 (d, 1H), 1.42 (s, 3H), 0.98 (s, 3H).

Intermediate BV:(1S,3S)—N-(5-fluoro-2-methylphenyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate BU (160 mg, 0.54 mmol) was reacted as described underGeneral Procedure E to furnish the title compound which was purified bycolumn chromatography (cyclohexane→70% EtOAc/cyclohexane) to give awhite solid (187 mg, 92%). ESIMS m/z [M+H]⁺377.2.

Intermediate BW:(1S,3S)—N-(4,5-difluoro-2-methylphenyl)-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate AP (180 mg, 0.94 mmol) and 4,5-difluoro-2-methylaniline(135 mg, 0.94 mmol) were reacted as described under General Procedure D.The crude material was purified by column chromatography to yield thedesired product as a white solid (263 mg, 89%). ¹H NMR (300 MHz, CDCl₃)δ 7.84-7.78 (m, 1H), 7.32-7.17 (m, 6H), 7.01-6.95 (m, 1H), 2.83 (d, 1H),2.25 (s, 3H), 1.86 (d, 1H), 1.41 (s, 3H), 0.98 (s, 3H).

Intermediate BX:(1S,3S)—N-(4,5-difluoro-2-methylphenyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate BW (260 mg, 0.82 mmol) was reacted as described underGeneral Procedure E to furnish the title compound which was purified bycolumn chromatography (cyclohexane→70% EtOAc/cyclohexane) to give awhite solid (242 mg, 74%). ESIMS m/z [M+H]⁺395.2.

Intermediate BY: ±transethyl-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate

Intermediate G (1.55 g, 7.10 mmol) was reacted as described underGeneral Procedure E to furnish the title compound which was purified bycolumn chromatography (30% EtOAc/hexane→100% EtOAc) to give the titlecompound as a glassy white solid (1.12 g, 53%). ESIMS m/z [M+NH₄]⁺315.2.

Intermediate BZ: ±trans4-[3-(hydroxymethyl)-2,2-dimethylcyclopropyl]benzenesulfonamide

To a cooled (0° C.) solution of Intermediate BY (1.07 g, 3.60 mmol) inEt₂O (51 ml) was added LiAlH₄ (575 mg, 14.4 mmol) in one portion. Thereaction mixture was stirred for 20 min at 0° C. before warming toambient temperature. After 2.5 h LCMS showed the reaction was completeand the reaction was cooled to 0° C. and quenched by careful addition ofpotassium sodium tartrate (1.0 M solution). The mixture was stirred atambient temperature for 1 h before neutralising with HCl (2 M), theproduct was extracted with EtOAc (4×) and the combined extracts washedwith brine (2×), dried (MgSO₄) and concentrated in vacuo. The productwas purified by column chromatography (80% EtOAc/hexane) to give thetitle compound as a white solid (742 mg, 81%). ESIMS m/z [M+NH₄]⁺273.2.

Intermediate CA: ±trans2,2-dimethyl-N-(2-methylpyridin-3-yl)-3-phenylcyclopropanecarboxamide

Intermediate H (350 mg, 1.8 mmol) and 3-amino-2-methylpyridine (195 mg,1.8 mmol) were reacted as described under General Procedure D. The crudematerial was purified by column chromatography (cyclohexane→10%EtOAc/cyclohexane) to give the title compound (500 mg, 99%) as a whitesolid. ESIMS m/z [M+H]⁺381.3

Intermediate CB: ±trans2,2-dimethyl-N-(2-methylpyridin-3-yl)-314-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate CA (500 mg, 1.78 mmol) was reacted as described underGeneral Procedure E to furnish the title compound which was purified bycolumn chromatography (cyclohexane→1:1 EtOAc/cyclohexane) to give thetitle compound as a white solid (200 mg, 25%). ESIMS m/z [M+H]⁺360.2.

Intermediate CC: ±transN-(4-fluoro-2-methylphenyl)-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate H (400 mg, 2.10 mmol) and 5-chloro-4-fluoro-2-methylaniline(408 mg, 3.00 mmol) were reacted as described under General Procedure D.The crude material was purified by column chromatography(cyclohexane→DCM) to yield the desired product as a white solid (770 mg,77%). ¹H NMR (300 MHz, CDCl₃) δ 7.92 (br d, 1H), 7.32-7.15 (m, 6H), 6.98(br d, 1H), 2.84 (d, J=5.4 Hz, 1H), 2.27 (s, 3H), 1.86 (d, 1H), 1.42 (s,3H), 0.98 (s, 3H).

Intermediate CD: ±transN-(4-fluoro-2-methylphenyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate CC (0.770 g, 2.3 mmol) was reacted as described underGeneral Procedure E to furnish the title compound which was purified bycolumn chromatography (cyclohexane→1:1 EtOAc/cyclohexane) to give thetitle compound as a white solid (750 mg, 80%). ESIMS m/z [M+H]⁺411.3.

Intermediate CE: ±transN-(2-ethyl-5-fluorophenyl)-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate H (300 mg, 1.5 mmol) and 2-ethyl-5-fluoroaniline (209 mg,1.5 mmol) were reacted as described under General Procedure D. The crudematerial was purified by column chromatography (cyclohexane→10%EtOAc/cyclohexane) to yield the desired product as a white solid (400mg, 86%). ESIMS m/z [M+H]⁺312.5.

Intermediate CF: ±transN-(2-ethyl-5-fluorophenyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate CE (400 mg, 1.28 mmol) was reacted as described underGeneral Procedure E to furnish the title compound which was purified bycolumn chromatography (cyclohexane→1:1 EtOAc/cyclohexane) to give thetitle compound as a white solid (500 mg, 100%). ESIMS m/z [M+H]⁺391.6.

Intermediate CG: ±transN-[2-fluoro-5-(trifluoromethoxy)phenyl]-2,2-dimethyl-3-phenylcyclopropanecarboxamideand Intermediate CH: ±transN-[5-fluoro-2-(trifluoromethoxy)phenyl]-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate H (400 mg, 2.10 mmol) and a mixture of2-fluoro-5-(trifluoromethoxy)aniline and5-fluoro-2-(trifluoromethoxy)aniline (ratio 45:55) (410 mg, 2.10 mmol)were reacted as described under General Procedure D. The crude materialwas purified by column chromatography (cyclohexane→5% EtOAc/cyclohexane)to yield two products, first eluting Intermediate CH (200 mg, 26%) as awhite solid and second eluting Intermediate CG (160 mg, 21%) as a whitesolid.

Intermediate CH: ¹H NMR (300 MHz, CDCl₃) δ 8.43 (br s, 1H), 7.62 (br s,1H), 7.33-7.08 (m, 6H), 6.92-6.87 (m, 1H), 2.87 (d, 1H), 1.88 (d, 1H),1.42 (s, 3H), 1.00 (s, 3H).

Intermediate CG: ¹H NMR (300 MHz, CDCl₃) δ 8.30 (br d, 1H), 7.65 (br s,1H), 7.34-7.15 (m, 6H), 6.82-6.75 (m, 1H), 2.86 (d, 1H), 1.86 (d, 1H),1.40 (s, 3H), 1.00 (s, 3H).

Intermediate CI: ±transN-[2-fluoro-6-(trifluoromethoxy)phenyl]-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate CG (200 mg, 0.45 mmol) was reacted as described underGeneral Procedure E to furnish the title compound which was purified bycolumn chromatography (cyclohexane→1:1 EtOAc/cyclohexane) to give thetitle compound as a white solid (200 mg, 83%). ¹H NMR (300 MHz, d₆-DMSO)δ 10.3 (br s, 1H), 8.21-8.18 (m, 1H), 7.76 (d, 2H), 7.44-7.38 (m, 3H),7.26 (br s, 2H), 7.14-7.11 (m, 1H), 2.66 (d, 1H), 2.61 (d, 1H), 1.32 (s,3H), 0.88 (s, 3H).

Intermediate CJ: ±transN-[5-fluoro-2-(trifluoromethoxy)phenyl]-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate CH (160 mg, 0.44 mmol) was reacted as described underGeneral Procedure E to furnish the title compound which was purified bycolumn chromatography (cyclohexane→1:1 EtOAc/cyclohexane) to give thetitle compound as a white solid (130 mg, 66%). ¹H NMR (300 MHz, d₆-DMSO)δ 10.1 (br s, 1H), 7.94 (dd, 1H), 7.76 (d, 2H), 7.49-7.44 (m, 1H), 7.38(d, 2H), 7.29 (br s, 1H), 7.05 (dq, 1H), 5.74 (s, 1H), 2.68-2.61 (m,2H), 1.30 (s, 3H), 0.88 (s, 3H).

Intermediate CK: ±trans4-(3-formyl-2,2-dimethylcyclopropyl)benzenesulfonamide

Intermediate BZ (560 mg, 2.2 mmol) was reacted as described underGeneral Procedure H to give the title compound which was purified bycolumn chromatography (100% cyclohexane→60% EtOAc/cyclohexane) tofurnish a colorless oil (409 mg, 73%). ¹H NMR (300 MHz, CDCl₃) δ 9.63(d, 1H), 7.87-7.84 (m, 2H), 7.33-7.30 (m, 2H), 5.00 (br s, 2H), 2.97 (d,1H), 2.26 (dd, 1H), 1.44 (s, 3H), 0.98 (s, 3H).

Intermediate CL: ±trans5-chloro-N-[(2,2-dimethyl-3-phenylcyclopropyl)methyl]-2-methoxyaniline

Intermediate X (348 mg, 2.0 mmol) and 5-chloro-2-methoxyaniline (315 mg,2.0 mmol) were reacted as described under General Procedure I to givethe title compound which was purified by column chromatography (100%cyclohexane→70% cyclohexane/DCM) to furnish a colorless oil (417 mg,66%). ¹H NMR (300 MHz, CDCl₃) δ 7.31-7.12 (m, 5H), 6.68-6.55 (m, 3H),4.52 (br s, 1H), 3.83 (s, 3H), 3.31 (dd, 1H), 3.21 (dd, 1H), 1.80 (d,1H), 1.63-1.57 (m, 1H), 1.29 (s, 3H), 0.87 (s, 3H).

Intermediate CM: ±transethyl-3-(4-bromophenyl)-2,2-dimethylcyclopropanecarboxylate

Isopropyltriphenylphosphonium iodide (17.7 g, 41 mmol) and ethyltrans-4-bromocinnamate (8.70 g, 34 mmol) were reacted as described underGeneral Procedure B to furnish the title compound (8.05 g, 79%) as acolorless oil (cyclohexane→cyclohexane/CH₂Cl₂, 1:1). ESIMS m/z[M+H]⁺297.0 and 299.3.

Intermediate CN: ±trans3-(4-bromophenyl)-2,2-dimethylcyclopropanecarboxylic acid

Intermediate CM (8.05 g, 27.1 mmol) was reacted as described underGeneral Procedure C to furnish the title compound as a white solid (7.1g, 97%). ¹H NMR (300 MHz, CDCl₃) δ 7.43-7.38 (m, 2H), 7.06-7.03 (m, 2H),6.68 (d, 1H), 1.92 (d, 1H), 1.42 (s, 3H), 0.94 (s, 3H).

Intermediate CO: ±trans3-(4-bromophenyl)-N-(5-chloro-2-methoxyphenyl)-2,2-dimethylcyclopropanecarboxamide

Intermediate CN (4.0 g, 14.9 mmol) and 5-chloro-2-methoxyaniline (2.6 g,16.3 mmol) were reacted as described under General Procedure D. Thecrude material was purified by column chromatography (cyclohexane→60%DCM/cyclohexane) to give the title compound (2.75 g, 45%) as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 8.52-8.48 (m, 1H), 7.97 (brs, 1H),7.42-7.40 (m, 2H), 7.09-7.06 (m, 2H), 6.99 (dd, 1H), 6.79 (d, 1H), 3.91(s, 3H), 2.77 (d, 1H), 1.83 (d, 1H), 1.39 (s, 3H), 0.97 (s, 3H).

Intermediate CP: ±transN-(5-chloro-2-methoxyphenyl)-3-2′-hydroxybiphenyl-4-yl)-2,2-dimethylcyclopropanecarboxamide

A mixture of Intermediate CO (204 mg, 0.50 mmol), 2-hydroxybenzeneboronic acid (138 mg, 1.00 mmol) and cesium fluoride (228 mg, 1.50 mmol)in anhydrous DME (5 ml) and MeOH (25 ml) was degassed with argon for 30minutes at ambient temperature. Pd(PPh₃)₄ (58 mg, 0.05 mmol) was addedand the mixture was degassed with argon for 15 minutes at roomtemperature before heating to 130° C. in the microwave for 20 minutes.After cooling, the reaction mixture was washed with NaHCO₃ (sat. aq.)and extracted with EtOAc. The organics were dried (MgSO₄) concentratedin vacuo. The crude material was purified by column chromatography(cyclohexane→cyclohexane/EtOAc, 1:1) to give the title compound as abrown solid (138 mg, 65%). ¹H NMR (300 MHz, CDCl₃) δ 8.52 (s, 1H), 8.00(s, 1H), 7.42-7.23 (m, 8H), 7.02-6.96 (m, 2H), 6.82-6.79 (m, 1H), 3.92(s, 3H), 2.88 (d, 1H), 1.92 (d, 1H), 1.44 (s, 3H), 1.05 (s, 3H).

Intermediate CQ: ±transN-[5-chloro-2-(trifluoromethyl)phenyl]-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate H (500 mg, 2.6 mmol) and5-chloro-2-(trifluoromethyl)aniline (508 mg, 2.6 mmol) were reacted asdescribed under General Procedure D to furnish the title compound whichwas used without purification in the next step.

Intermediate CR: ±transN-[5-chloro-2-(trifluoromethyl)phenyl]-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate CQ (400 mg, 1.09 mmol) was reacted as described underGeneral Procedure E to furnish the title compound as a white solid (150mg, 13% over two steps) after purification by column chromatography. ¹HNMR (300 MHz, CDCl₃) δ 8.33 (br s, 1H), 7.89-7.83 (m, 2H), 7.66 (br s,1H), 7.55 (d, 1H), 7.32 (t, 2H), 7.23-7.20 (m, 1H), 4.81-4.79 (m, 2H),2.90 (d, 1H), 1.91 (d, 1H), 1.41 (s, 3H), 0.99 (s, 3H).

Intermediate CS: ±transN-{5-chloro-2-methoxyphenyl)-2,2-dimethyl-3-(4-[(methylsulfonyl)amino]phenyl}cyclopropanecarboxamide

A mixture of potassium phosphate (233 mg, 1.1 mmol), Pd₂(dba)₃ (10 mg,0.01 mmol), and f-BuXPhos (13 mg, 0.03 mmol) in anhydrous 1,4-dioxane (4ml) was degased with argon for 5 minutes at ambient temperature and thenheated at 80° C. for 30 minutes. After cooling, Intermediate CO (409 mg,1.0 mmol) and methanesulfonamide (114 mg, 1.2 mmol) were added and themixture was stirred under argon at 80° C. for 15 h. After cooling, thereaction medium was taken in ethyl acetate and washed with a solution of1N HCl. The organic phase was dried over Na₂SO₄ and concentrated invacuo. The reaction mixture was directly purified by columnchromatography (100% cyclohexane 60% EtOAc/cyclohexane) leading to theexpected product as a white solid (251 mg, 59%). ¹H NMR (300 MHz, CDCl₃)δ 8.50 (br s, 1H), 7.98 (br s, 1H), 7.21-7.13 (m, 4H), 6.99 (dd, 1H),6.80 (d, 1H), 6.38 (br s, 1H), 3.92 (s, 3H), 3.00 (s, 3H), 2.80 (d, 1H),1.84 (d, 1H), 1.40 (s, 3H), 0.98 (s, 3H). ESIMS m/z [M+H]⁺423.2.

Intermediate CT: ±transethyl-2-(4-sulfamoylphenyl)spiro[2,4]heptane-1-carboxylate

Intermediate Q (3.5 g, 14.3 mmol) was reacted as described under GeneralProcedure E to furnish the title compound as a white solid (1.5 g, 33%)after purification by column chromatography. ¹H NMR (300 MHz, CDCl₃) δ7.84 (d, 2H), 7.24 (d, 2H), 4.88 (br s, 2H), 4.23-4.13 (m, 2H), 2.79 (d,1H), 2.20 (d, 1H), 1.91-1.85 (m, 2H), 1.74-1.42 (m, 6H), 1.30 (t, 3H).

Intermediate CU: ±trans4-[2-(hydroxymethyl)spiro[2,4]hept-1-yl]benzenesulfonamide

Intermediate CT (1.5 g, 4.6 mmol) was reacted as described under GeneralProcedure G, (except 2.2 eq of LiAlH₄ was used) to furnish the titlecompound as a white solid (1.01 g, 77%) which was used crude in the nextstep. ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, 2H), 7.20 (d, 2H), 5.29 (br s,2H), 3.84 (dd, 1H), 3.72 (dd, 1H), 1.96-1.12 (m, 10H).

Intermediate CV: ±trans4-[2-formylspiro[2,4]hept-1-yl]benzenesulfonamide

Intermediate CU (900 mg, 3.2 mmol) was reacted as described underGeneral Procedure H to give the title compound which was purified bycolumn chromatography (100% cyclohexane→60% EtOAc/cyclohexane) tofurnish a colorless oil (701 mg, 78%). ¹H NMR (300 MHz, CDCl₃) δ 9.50(d, 1H), 7.85 (d, 2H), 7.25 (d, 2H), 5.03 (br s, 2H), 2.98 (d,), 2.45(dd, 1H), 2.03-1.88 (m, 3H), 1.82-1.47 (m, 4H), 1.40-1.25 (m, 1H).

Intermediate CW: methyl(1S,3S)-2,2-dimethyl-3-phenylcyclopropanecarboxylate

To a solution of Intermediate AP (0.602 g, 3.16 mmol) in methanol (12ml) was added trimethyl orthoformate (3.4 eq. 1.2 ml) and sulphuric acid(cat., 6 drops). The solution was heated under reflux overnight. Thereaction mixture was concentrated in vacuo and EtOAc added. The organicswere washed with H₂O (2×), NaHCO₃ (sat. aq., 2×) dried (MgSO₄) andconcentrated in vacuo. The product was used crude in the next stepwithout further purification (606 mg, 94%). ESIMS m/z [M+H]⁺205.2.

Intermediate CX: methyl(1S,3S)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate

Intermediate CW (0.596 g, 2.92 mmol) was reacted as described underGeneral Procedure E to furnish the title compound as a clear oil (269mg, 33%) after purification by column chromatography (35% EtOAc/hexane).ESIMS m/z [M−H]⁻282.3.

Intermediate CY:4-[(1S,3S)-3-(hydroxymethyl)-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate CX (0.259 g, 0.91 mmol) was reacted as described forIntermediate BZ to furnish the title compound as a white solid (197 mg,85%) after purification by trituration and column chromatography (60%EtOAc/hexane). ESIMS m/z [M+NH₄]⁺273.2.

Intermediate CZ: methyl(1R,3R)-2,2-dimethyl-3-phenylcyclopropanecarboxylate

Intermediate AO (0.605 g, 3.18 mmol) was reacted as described forIntermediate CW to furnish the title compound which was used crude inthe next step (619 mg, 95%). ESIMS m/z [M+H]⁺205.2.

Intermediate DA: methyl(1R,3R)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxylate

Intermediate CZ (0.609 g, 2.98 mmol) was reacted as described underGeneral Procedure E to furnish the title compound as a clear oil (205mg, 24%) after purification by column chromatography (35% EtOAc/hexane).ESIMS m/z [M−H]⁻282.3.

Intermediate DB:4-[(1R,3R)-3-(hydroxymethyl)-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate DA (0.202 g, 0.71 mmol) was reacted as described forIntermediate BZ to furnish the title compound as a white solid (160 mg,88%) after purification by trituration and column chromatography (60%EtOAc/hexane). ESIMS m/z [M+NH₄]⁺273.2.

Intermediate DC:(1S,2S)—N-[5-fluoro-2-(trifluoromethoxy)phenyl]-2-phenylcyclopropanecarboxamide

Intermediate AK (250 mg, 1.31 mmol) and 5-fluoro-2-(trifluoromethoxy)aniline (255 mg, 1.31 mmol) were reacted as described under GeneralProcedure D to furnish the title compound as a white solid (226 mg, 51%)after purification by column chromatography (100% cyclohexane→EtOAc). ¹HNMR (300 MHz, CDCl₃) δ 8.40 (br s, 1H), 7.60 (br s, 1H), 7.33-7.20 (m,4H), 7.15-7.06 (m, 2H), 6.92-6.87 (m, 1H), 2.66-2.60 (m, 1H), 1.82-1.73(m, 2H), 1.48-1.38 (m, 1H).

Intermediate DD:(1S,2S)—N-[5-fluoro-2-(trifluoromethoxy)phenyl]-2-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate DC (270 mg, 0.80 mmol) was reacted as described underGeneral Procedure E to furnish the title compound as a white solid (190mg, 57%) after purification by column chromatography (cyclohexane→50%EtOAc/cyclohexane). ¹H NMR (300 MHz, d₆-DMSO) δ 10.17 (br s, 1H), 7.99(dd, 1H), 7.72 (d, 2H), 7.47-7.41 (m, 1H), 7.35 (d, 2H), 7.88 (br s,2H), 7.08-7.04 (m, 1H), 2.57-2.44 (m, 2H), 1.57-1.44 (m, 2H).

Intermediate DE:(1R,2R)—N-[5-fluoro-2-(trifluoromethoxy)phenyl]-2-phenylcyclopropanecarboxamide

Intermediate AL (250 mg, 1.31 mmol) and 5-fluoro-2-(trifluoromethoxy)aniline (255 mg, 1.31 mmol) were reacted as described under GeneralProcedure D to furnish the title compound as a white solid (183 mg, 35%)after purification by column chromatography (100% cyclohexane→EtOAc). ¹HNMR (300 MHz, CDCl₃) δ 8.40 (br s, 1H), 7.60 (br s, 1H), 7.33-7.20 (m,4H), 7.15-7.06 (m, 2H), 6.92-6.87 (m, 1H), 2.66-2.60 (m, 1H), 1.82-1.73(m, 2H), 1.48-1.38 (m, 1H).

Intermediate DF:(1R,2R)—N-[5-fluoro-2-(trifluoromethoxy)phenyl]-2-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate DE (190 mg, 0.56 mmol) was reacted as described underGeneral Procedure E to furnish the title compound as a white solid (120mg, 51%) after purification by column chromatography (cyclohexane→50%EtOAc/cyclohexane). ¹H NMR (300 MHz, d₆-DMSO) δ 10.17 (br s, 1H), 7.99(dd, 1H), 7.72 (d, 2H), 7.47-7.41 (m, 1H), 7.35 (d, 2H), 7.88 (br s,2H), 7.08-7.04 (m, 1H), 2.57-2.44 (m, 2H), 1.57-1.44 (m, 2H).

Intermediate DG: ±trans 2-benzylcyclopropanecarboxylic acid

2-(Phenylmethyl)cyclopropane carboxylic acid, ethyl ester (1.0 g, 4.9mmol) was reacted as described under General Procedure C to furnish thetitle compound (840 mg, 97%) as a yellow oil which was used withoutpurification in the next step. ¹H NMR (300 MHz, CDCl₃) b 7.29-7.18 (m,5H), 2.96-2.89 (m, 2H), 1.82 (ddd, 1H), 1.62 (sextet, 1H), 1.26-1.15 (m,2H).

Intermediate DH: t trans2-benzyl-N-(5-chloro-2-methoxyphenyl)cyclopropanecarboxamide

Intermediate DG (0.80 g, 4.5 mmol) and 5-chloro-2-methoxyaniline (1.4 g,9.0 mmol) were reacted as described under General Procedure D to furnishthe title compound as a white solid (1.5 g, 97%) after purification bycolumn chromatography. ESIMS m/z [M+H]⁺316.5.

Intermediate DI: ±transN-(5-chloro-2-methoxyphenyl)-2-(4-sulfamoylbenzyl)cyclopropanecarboxamide

Intermediate DH (1.5 g, 4.5 mmol) was reacted as described under GeneralProcedure E to furnish the title compound as a white solid (1.1 g, 62%)after purification by column chromatography: ESIMS m/z [M+H]⁺395.2.Mp=182-184° C.

Intermediate DJ: ±trans4-{3-[(5-chloro-2-methoxyphenyl)carbamoyl]-2,2-dimethylcyclopropyl}benzenesulfonylchloride

To a solution of chlorosulfonic acid (7.13 ml) at 0° C. was addedIntermediate I (2.95 g, 8.94 mmol) portion-wise. The reaction mixturewas allowed to slowly come to ambient temperature and stirred for 1 h.The reaction mixture was then poured onto ice-water with rapid stirringand the resulting precipitated collected by vacuum filtration and driedunder vacuum. This material was used without further purification (3.28g, 86%). ESIMS m/z [M+H]⁻428.0.

Intermediate DK: ±transN-(5-chloro-2-methoxyphenyl)-3-[4-(hydroxysulfamoyl)phenyl]-2,2-dimethylcyclopropanecarboxamide

To a solution of hydroxylamine hydrochloride (0.405 g, 5:83 mmol) andK₂CO₃ (811 mg, 5.86 mmol) in anhydrous THF was added Intermediate DJ,(250 mg, 0.58 mmol) portion-wise and the mixture stirred for 3 h. Afterthis time the reaction was not proceeding so H₂O (2 ml) was added to aidin dissolution. After 1 hour the reaction was complete. The water wasremoved and the organics concentrated in vacuo. The crude residue waspurified directly by column chromatography (50-100% EtOAc/hexane,R_(f)=0.45 in 60% EtOAc/hexane) to furnish the title compound (62 mg,25% yield, 90% pure by LCMS at 254 nm). ESIMS m/z [M+H]⁺425.0.

Intermediate DL: ±transN-(5-chloro-2-methoxyphenyl)-3-[4-(hydrazinylsulfonyl)phenyl]-2,2-dimethylcyclopropanecarboxamide

To a solution of hydrazine hydrate (1.032 g, 20.6 mmol) in THF was addedIntermediate DJ (250 mg, 0.58 mmol) portion-wise and the mixture stirredfor 15 minutes. The precipitated amine hydrochloride was removed byvacuum filtration and the mixture concentrated in vacuo. The cruderesidue was triturated with EtOAc and then Et₂O to get some of theproduct clean while the residue was purified by column chromatography(80% EtOAc/hexane, R, =0.58) which was combined with the trituratedmaterial to give the title compound (212 mg, 86%). ESIMS m/z[M+H]⁻424.0.

Intermediate DM:±trans[3-(4-bromophenyl)-2,2-dimethylcyclopropyl]methanol

Intermediate CM (4.07 g, 13.7 mmol) was suspended in anhydrous Et₂O (120ml) under an atmosphere of nitrogen and was cooled to 0° C. LiAlH₄ (1.09g, 27.4 mmol) was added in one portion and the mixture stirred at 0° C.for 20 min before warming to room temperature and stirring overnight.The mixture was cooled to 0° C. and potassium sodium tartratetetrahydrate solution (1 M, 30 ml) was added slowly. The reactionmixture was stirred at RT for 1 h before addition of HCl (2M aq.) wasadded to neutralise the solution. The product was extracted with Et₂O(4×) and the combined extracts washed with bring (2×), dried (MgSO₄) andconcentrated in vacuo. The product was purified by column chromatography(20% EtOAc/hexane 100% EtOAc) to yield 2.92 g (84%) of the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ 7.40-7.36 (m, 2H), 7.06-7.01 (m,2H), 3.89 (dd, 1H), 3.74-3.67 (dd, 1H), 1.70 (d, 1H), 1.43-1.36 (m, 1H),1.28 (s, 3H), 0.84 (s, 3H).

Intermediate DN: ±trans3-(4-bromophenyl)-2,2-dimethylcyclopropanecarbaldehyde

DMSO (0.31 ml, 0.340 g, 4.35 mmol) was added drop-wise to a solution ofoxalyl chloride (0.19 ml, 0.274 g, 2.16 mmol) in anhydrous DCM (10 ml)at −78° C. under an atmosphere of nitrogen. The solution was stirred at−78° C. for 30 minutes before addition of a solution of Intermediate DM(0.500 g, 1.96 mmol) in anhydrous DCM (5 ml) drop-wise. The reactionmixture was stirred at −78° C. for 1.5 h before addition of NEt₃ (1.4ml, 0.999 g, 9.88 mmol) drop-wise. The solution was warmed to roomtemperature and stirred overnight. The reaction was quenched by theaddition of H₂O and the product extracted with DCM (3×). The combinedextracts were washed with brine, dried (MgSO₄) and concentrated in vacuoto give the title compound (481 mg, 97%) which was used withoutpurification in the next step.

Intermediate DO: ±transN-([3-(4-bromophenyl)-2,2-dimethylcyclopropyl]methyl)-5-chloro-2-methoxyaniline

Intermediate DN (0.481 g, 1.90 mmol) was dissolved in anhydrous THF (13ml) under an atmosphere of nitrogen. 5-Chloro-2-methoxyaniline (0.314 g,2.00 mmol) was added followed by acetic acid (0.33 ml, 0.342 g, 5.70mmol) and NaBH(OAc)₃ (0.805 g, 3.80 mmol) and the reaction mixture wasstirred at ambient temperature. After 1 h the reaction was quenched byaddition of NaHCO₃ (sat. aq.) and the mixture stirred for 15 minutes.The layers were separated and the aqueous phase extracted further withDCM (2×). The combined extracts were washed with brine, dried (MgSO₄)and concentrated in vacuo. The product was purified by columnchromatography (100% hexane 50% DCM/hexane) to give 188 mg (25%) of thetitle compound. ¹H NMR (300 MHz, CDCl₃) δ 7.40-7.37 (m, 2H), 7.05-7.02(m, 2H), 6.67-6.57 (m, 3H), 4.31 (br s, 1H), 3.83 (s, 3H), 3.29 (dd,1H), 3.19 (dd, 1H), 1.73 (d, 1H), 1.42-1.35 (m, 1H), 1.30 (s, 3H), 0.85(s, 3H).

Intermediate DP: transN-(2,2-difluorocyclohexyl)-2,2-dimethyl-3-phenylcyclopropanecarboxamide

Intermediate H (0.204 g, 1.07 mmol) and 2,2-difluorocyclohexaneaminehydrochloride (0.193 g, 1.13 mmol) were reacted as described underGeneral Procedure J to furnish the title compound (0.352 g), as adiastereomeric pair, which was used crude in subsequent reactions. ESIMSm/z [M+H]⁺308.3.

Intermediate DQ: transN-(2,2-difluorocyclohexyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopropanecarboxamide

Intermediate DP (0.352 g) was reacted as described under GeneralProcedure E to furnish the title compound (0.415 g), as a diastereomericpair, which was used crude in subsequent reactions. ESIMS m/z[M+H]⁺387.0.

Example 1 ±trans4-(2-{[(5-chloro-2-methoxyphenyl)amino]methyl}cyclopropyl)benzenesulfonamide

Intermediate B (180 mg, 0.47 mmol) was reacted as described underGeneral Procedure F to furnish the title compound (88 mg, 51%) as awhite solid. ¹H NMR (300 MHz, CDCl₃+1 drop DMSO-d₆) δ 7.77-7.72 (m, 2H),7.11-7.07 (m, 2H), 6.60-6.51 (m, 2H), 6.47 (d, 1H), 5.88 (s, 2H),4.43-4.26 (m, 1H), 3.76 (s, 3H), 3.10 (t, 2H), 1.86-1.82 (m, 1H),1.47-1.41 (m, 1H), 1.04-0.99 (m, 2H). ESIMS m/z [M+H]⁺367.0.

Example 2 ±trans4-(2-{[(3,4-difluorophenyl)amino]methyl}cyclopropyl)benzenesulfonamide

Intermediate F (293 mg, 0.83 mmol) was reacted as described underGeneral Procedure F to furnish the title compound (138 mg, 49%) as awhite solid. ¹H NMR (300 MHz, CDCl₃) δ 7.84-7.80 (m, 2H), 7.19-7.15 (m,2H), 7.01-6.91 (m, 1H), 6.43-6.36 (m, 1H), 6.30-6.24 (m, 1H), 4.74 (s,2H), 3.78 (bra, 1H), 3.12 (d, 2H), 1.91 (ddd, 1H), 1.55-1.44 (m, 1H),1.11-1.06 (m, 2H). ESIMS m/z [M+H]⁺339.0.

Example 3 trans4-(2-{[(4-fluorophenyl)amino]methyl}cyclopropyl)benzenesulfonamide

Intermediate D (271 mg, 0.81 mmol) was reacted as described underGeneral Procedure F to furnish the title compound, recrystalisation fromethylacetate/dichloromethane gave (56 mg, 22%) as a white solid. ¹H NMR(300 MHz, CDCl₃+1 drop DMSO-d₆) δ 7.67-7.72 (m, 2H), 7.11-7.06 (m, 2H),6.87-6.79 (m, 2H), 6.55-6.46 (m, 2H), 5.84 (s, 2H), 3.77 (brs, 1H),3.14-3.02 (m, 2H), 1.84 (ddd, 1H), 1.49-1.39 (m, 1H), 1.04-0.97 (m, 2H).ESIMS m/z [M+H]⁺321.2.

Example 4 ±trans4-(3-{[(5-chloro-2-methoxyphenyl)amino]methyl}-2,2-dimethylcyclopropyl)benzenesulfonamide

Intermediate J (200 mg, 0.49 mmol) was reacted as described underGeneral Procedure F to give the title compound (90 mg, 47%) as a whitesolid.

Alternatively Intermediate CL (415 mg, 1.3 mmol) was reacted asdescribed under General Procedure E to give the title compound (141 mg,27%) as a white solid. ¹H NMR (300 MHz, d₆-DMSO) δ 7.68 (d, 2H), 7.31(d, 2H), 7.26 (s, 2H), 6.76 (d, 1H), 6.57 (d, 1H), 6.51 (dd,), 5.07-5.03(m, 1H), 3.75 (s, 3H), 3.26-3.14 (m, 2H), 1.86 (d, 1H), 1.62-1.50 (m,1H), 1.25 (s, 3H), 0.77 (s, 3H). mp 186-188° C. ESIMS m/z [M+H ]⁺395.0.

Example 5 ±trans4-{2,2-dimethyl-3-[(phenylamino)methyl]cyclopropyl}benzenesulfonamide

Intermediate L (170 mg, 0.5 mmol) was reacted as described under GeneralProcedure F to give the title compound (90 mg, 55%) as a white solid. ¹HNMR (300 MHz, CD₃OD) δ 7.77 (dd, 2H), 7.30 (d, 2H), 7.14-7.08 (m, 2H),6.73-6.60 (m, 3H), 3.29-3.25 (m, 2H), 1.88 (d, 1H), 1.56-1.53 (m, 1H),1.32 (s, 3H), 0.83 (s, 3H). ESIMS m/z [M+H]⁺331.1.

Example 6 ±trans4-(2,2-dimethyl-3-{[methyl(phenyl)amino]methyl}cyclopropyl)benzenesulfonamide

Intermediate N (250 mg, 0.7 mmol) was reacted as described under GeneralProcedure F to give the title compound (90 mg, 37%) as a colourless oil.¹H NMR (300 MHz, CD₃OD) δ 7.75-7.72 (m, 2H), 7.23-7.16 (m, 4H),6.88-6.85 (m, 2H), 6.71-6.66 (m, 1H), 3.63 (dd, 1H), 3.44 (dd, 1H), 2.94(s, 3H), 1.87 (d, 1H), 1.41-1.34 (m, 1H), 1.30 (s, 3H), 0.79 (s, 3H).ESIMS m/z [M+H]⁺345.2.

Example 7 ±trans4-(3-{[(5-chloro-2-methoxyphenyl)(methyl)amino]methyl}-2,2-dimethylcyclopropyl)benzenesulfonamide

Intermediate P (160 mg, 0.37 mmol) was reacted as described underGeneral Procedure F to give the title compound (133 mg, 88%) as a whitesolid. ¹H NMR (300 MHz, d₆-DMSO) δ 7.67 (d, 2H), 7.26-7.23 (m, 4H),6.88-6.83 (m, 3H), 3.76 (s, 3H), 3.30-3.16 (m, 2H), 2.75 (s, 3H), 1.70(d, 1H), 1.38-1.33 (m, 1H), 1.07 (s, 3H), 0.70 (s, 3H). ESIMS m/z[M+H]⁺409.1.

Example 8 trans4-(2-{[(5-chloro-2-methoxyphenyl)amino]methyl}spiro[2,4]hept-1-yl)benzenesulfonamide

Intermediate T (50 mg, 0.1 mmol) was reacted as described under GeneralProcedure F to give the title compound (9 mg, 36%) as a white solid. ¹HNMR (300 MHz, CD₃OD) δ 7.78 (d, 2H), 7.26 (d, 2H), 6.73 (d, 1H),6.60-6.53 (m, 2H), 3.80 (s, 3H), 3.24 (m, 2H), 2.00 (d, J=5.6 Hz, 1H),1.93-1.86 (m, 1H), 1.80-1.39 (m, 7H), 1.29-1.18 (m, 1H). ESIMS m/z[M+H]⁺421.1.

Example 9 ±trans4-(2-{[(2,6-dimethoxypyridin-3-yl)amino]methyl}spiro[2,4]hept-1-yl)benzenesulfonamide

Intermediate V (20 mg, 0.05 mmol) was reacted as described under GeneralProcedure F to give the title compound (15.5 mg, 79%) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 7.70-7.66 (m, 2H), 7.26-7.19 (m, 4H),6.96-6.93 (m, 1H), 6.12-6.09 (m, 1H), 4.33-4.27 (m, 1H), 3.85 (s, 3H),3.72 (s, 3H), 3.15-3.11 (m, 2H), 1.95 (d, 1H), 1.82-1.38 (m, 8H),1.12-1.06 (m, 1H). ESIMS m/z [M+H]⁺418.2. Mp=56-58° C.

Example 10 ±trans4-[3-{[(5-fluoropyridin-3-yl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate Z (385 mg) was reacted as described under General ProcedureF to give the title compound (4.5 mg, 1.2% yield) pure after two pTLCpurifications (50% EtOAc/CHCl₃). ¹H NMR (300 MHz, CDCl₃) δ 7.95-7.78 (m,4H), 7.28 (d, 2H), 6.63 (d, 1H), 4.90 (br s, 2H), 3.98 (br s, 1H),3.35-3.23 (m, 2H), 1.86 (d, 1H), 1.50 (apt q, 1H), 1.33 (s, 3H), 0.87(s, 311). ESIMS m/z [M+H]⁺350.3

Example 11 ±trans4-[2,2-dimethyl-3-({[2-(trifluoromethyl)pyridin-4-yl]amino}methyl)cyclopropyl]benzenesulfonamide

Intermediate AB (423 mg) was reacted as described under GeneralProcedure F to give the title compound (10.8 mg, 2.7%) pure after twopTLC purifications (60% EtOAc/hexane then 50% EtOAc/hexane). ¹H NMR (300MHz, CDCl₃+2 drops of d₆-DMSO) δ 8.19 (d, 1H), 7.78-7.75 (m, 2H),7.25-7.18 (m, 2H), 6.82 (d, 1H), 6.53 (dd, 1H), 5.97 (s, 2H), 5.33 (brt, 1H), 3.29-3.24 (m, 2H), 1.79 (d, 1H), 1.44-1.37 (m, 1H), 1.25 (s,3H), 0.80 (m, 3H). ESIMS m/z [M+H]⁺400.0.

Example 12 ±trans4-[2-({[5-(trifluoromethyl)pyridin-2-yl]amino}methyl)cyclopropyl]benzenesulfonamide

Intermediate AD (51 mg) was reacted as described under General ProcedureF to give the title compound (9 mg, 17%) purified by pTLC (60%EtOAc/CHCl₃). ¹H NMR (300 MHz, d₆-DMSO) δ 8.28 (br s, 1H), 7.72-7.48 (m,4H), 7.34-7.18 (m, 4H), 6.59 (d, 1H), 3.50-320 (m, 2H), 2.10-1.86 (m,1H), 1.55-1.40 (m, 1H), 1.32-1.25 (m, 1H), 1.10-0.88 (m, 1H). ESIMS m/z[M+H]⁺372.0.

Example 13 ±trans4-[3-{[(4-fluorophenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate AF was reacted as described under General Procedure F togive the title compound as a white solid (71 mg, 19% over 3 steps) aftercolumn chromatography (33% EtOAc/hexane) and pTLC (20% EtOAc/CHCl₃). ¹HNMR (300 MHz, CDCl₃) δ 7.83-7.81 (m, 2H), 7.29-7.26 (m, 3H), 6.93-6.88(m, 2H), 6.61-6.57 (m, 211), 4.86 (br s, 2H), 3.32-3.19 (m, 2H), 1.83(d, 1H), 1.49 (q, 1H), 1.31 (s, 3H), 0.86 (s, 3H). ESIMS m/z[M+H]⁺349.2.

Example 14 ±trans4-[3-{[(3,4-difluorophenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate AH was reacted as described under General Procedure F togive the title compound as a white solid (163 mg, 42% over 3 steps)after column chromatography (5% EtOAc/DCM then 10% EtOAc/DCM) followedby recrystallization from CHCl₃/pentane. ¹H NMR (300 MHz, CDCl₃) δ7.85-7.81 (m, 2H), 7.29-7.26 (m, 2H), 6.96 (dt, 1H), 6.46-6.39 (m, 1H),6.33-6.27 (m, 1H), 4.84 (br s, 2H), 3.67 (br s, 1H), 3.30-3.16 (m, 2H),1.83 (d,), 1.48 (q, 1H), 1.31 (s, 3H), 0.86 (s, 3H). ESIMS m/z[M+H]⁺367.3.

Example 154-[(1R,3R)-3({[4-fluoro-2-(trifluoromethyl)phenyl]amino}methyl)-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate AR (382 mg) was reacted as described under GeneralProcedure F to give the title compound (113 mg, 23%, over 2 steps) as awhite crystalline solid after purification by pTLC (40% EtOAc/hexane).¹H NMR (300 MHz, CDCl₃) δ 7.86-7.82 (m, 2H), 7.30-7.27 (m, 2H), 7.19(dd, 1H), 7.12 (dt, 1H), 6.71 (dd, 1H), 4.89-4.87 (m, 2H), 4.25 (brs,1H), 3.42 (dd, 1H), 3.21 (dd, 1H), 1.87 (d, 1H), 1.52 (ddd, 1H), 1.32(s, 3H), 0.87 (s, 3H). ESIMS [M+H]⁺417.0.

Example 164-[(1R,3R)-3-({[6-fluoro-2-(2,2,2-trifluoroethoxyl)phenyl]amino}methyl)-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate AT (435 mg) was reacted as described under GeneralProcedure F to give the title compound (156 mg, 31%, over 2 steps) as apale pink gum after purification by pTLC (40% EtOAc/hexane). ¹H NMR (300MHz, CDCl₃) δ 7.85-7.81 (m, 2H), 7.30-7.26 (m, 2H), 6.71 (dd, 1H), 6.38(dd, 1H), 6.31 (dt, 1H), 4.95 (brs, 2H), 4.40-4.10 (m, 3H), 3.35 (dd,1H), 3.19 (dd, 1H), 1.86 (d, 1H), 1.51 (dt, 1H), 1.32 (s, 3H), 0.87 (s,3H). ESIMS m/z [M+H]⁺447.3.

Example 174-[1S,3S)-3-({[4-fluoro-2-(trifluoromethyl)phenyl]amino}methyl)-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate AV (299 mg) was reacted as described under GeneralProcedure F to give the title compound (143 mg, 49%) as a whitecrystalline solid after purification by pTLC (40% EtOAc/hexane). ¹H NMR(300 MHz, CDCl₃) δ 7.86-7.82 (m, 2H), 7.30-7.27 (m, 2H), 7.19 (dd, 1H),7.12 (dt, 1H), 6.71 (dd, J=1H), 4.76 (brs, 2H), 4.25 (brs, 1H), 3.42(dd, 1H), 3.21 (dd, 1H), 1.87 (d, 1H), 1.56-1.49 (m, 1H), 1.32 (s, 3H),0.87 (s, 3H). ESIMS m/z [M+H]⁺417.0.

Example 184-[(1R,2R)-2-{[(4-fluorophenyl)amino]methyl}cyclopropyl]benzenesulfonamide

Intermediate AX was reacted as described under General Procedure F togive the title compound (80 mg, 21%) as a crystalline powder afterpurification by column chromatography (40% 60% EtOAc/hexane). ¹H NMR(300 MHz, CDCl₃+1 drop DMSO-d₆) δ 7.67-7.72 (m, 2H), 7.11-7.06 (m, 2H),6.87-6.79 (m, 2H), 6.55-6.46 (m, 2H), 5.84 (s, 2H), 3.77 (brs, 1H),3.14-3.02 (m, 2H), 1.84 (ddd, 1H), 1.49-1.39 (m, 1H), 1.04-0.97 (m, 2H).ESIMS m/z [M+H]⁺321.2.

Example 194-[(1R,2R)-2-({[5-(trifluoromethyl)pyridin-2-yl]amino}methyl)cyclopropyl]benzenesulfonamide

Intermediate AZ was reacted as described under General Procedure F togive the title compound (6 mg, 3.5%, with a 10% impurity) after twocolumns (50% EtOAc/DCM and 60% EtOAc/hexane) and one pTLC (40%EtOAc/CHCl₃). R_(f)=0.40 in 60% EtOAc/hexane. ¹H NMR (300 MHz, d₃-MeOD)δ 8.21 (br s, 1H), 7.77-7.73 (m, 2H), 7.59-7.55 (m, 1H), 7.26-7.20 (m,2H), 6.60 (d, 1H), 3.43 (d, 2H), 2.03-1.96 (m, 1H), 1.60-1.49 (m, 1H),1.22-1.03 (m, 2H). ESIMS m/z [M+H]⁺372.0.

Example 204-[(1R,3R)-3-([(5-chloro-2-methoxyphenyl)amino]methyl)-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate BB (526 mg) was reacted as described under GeneralProcedure F to give the title compound (239 mg, 47%) as a whitecrystalline solid after purification by column chromatography (30%EtOAc/hexane). ¹H NMR (300 MHz, d₆-DMSO) δ 7.73-7.65 (m, 2H), 7.31 (d,2H), 7.23 (s, 2H), 6.76 (d, 1H), 6.58-6.50 (m, 2H), 5.04-5.00 (m, 1H),3.75 (s, 3H), 3.22 (dt, 2H), 1.86 (d, 1H), 1.56 (q, 1H), 1.26 (s, 3H),0.78 (s, 3H). ESIMS m/z [M+H]⁺395.1.

Example 214-[(1S,3S)-3-{[(5-chloro-2-methoxyphenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate BD (342 mg) was reacted as described under GeneralProcedure F to give the title compound (149 mg, 45%) as a whitecrystalline solid after purification by column chromatography (33%EtOAc/hexane). ¹H NMR (300 MHz, d₆-DMSO) δ 7.73-7.65 (m, 2H), 7.31 (d,2H), 7.22 (s, 2H), 6.76 (d, 1H), 6.58-6.50 (m, 2H), 5.04-5.00 (m, 1H),3.75 (s, 3H), 3.22 (dt, 2H), 1.86 (d, 1H), 1.56 (q, 1H), 1.26 (s, 3H),0.78 (s, 3H). ESIMS m/z [M+H]⁺395.1.

Example 22 ±trans4-[3-{[(6-chloro-2-methylphenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate BF (150 mg, 0.48 mmol) was reacted as described underGeneral Procedure F to give the title compound (90 mg, 56%) as a whitesolid after column chromatography. ¹H NMR (300 MHz, d₆-DMSO) δ 7.68 (d,2H), 7.30 (d, 2H), 7.21 (s, 2H), 6.93 (d, 1H), 6.58 (d, 1H), 6.48 (dd,1H), 5.05 (t, 1H), 3.30-3.13 (m, 2H), 2.05 (s, 3H), 1.87 (d, 1H), 1.54(q, 1H), 1.27 (s, 3H), 0.78 (s, 3H). ESIMS m/z [M+H]⁺379.1. Mp=60-62° C.

Example 23 ±trans4-[3-{[(5-fluoro-2-methoxyphenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate BH (150 mg, 0.38 mmol) was reacted as described underGeneral Procedure F to give the title compound (70 mg, 49%) as a whitesolid after column chromatography. ¹H NMR (300 MHz, d₆-DMSO) δ 7.68 (d,2H), 7.31 (d, 2H), 7.22 (s, 2H), 6.73 (dd, 1H), 6.42 (dd, 1H), 6.25 (dt,1H), 5.03 (m, 1H), 3.73 (s, 3H), 3.22 (m, 2H), 1.87 (d, 1H), 1.56 (q,1H), 1.26 (s, 3H), 0.77 (s, 3H). ESIMS m/z [M+H]⁺379.1. Mp=164-166° C.

Example 24 ±trans4-(3-{[(3-chlorophenyl)amino]methyl}-2,2-dimethylcyclopropyl)benzenesulfonamide

Intermediate BJ (100 mg, 0.22 mmol) was reacted as described underGeneral Procedure F to give the title compound (35 mg, 36%) as a whitefoam after purification by column chromatography and semi-preperativeHPLC. ¹H NMR (300 MHz, d₆-DMSO) δ 7.69 (d, 2H), 7.33 (d, 2H), 7.22 (s,2H), 7.05 (t, 1H), 6.63-6.62 (m, 1H), 6.56 (dd, 1H), 6.50 (dd, 1H), 5.94(t, 1H), 3.23-3.11 (m, 2H), 1.85 (d, 1H), 1.46 (q, 1H), 1.25 (s, 3H),0.79 (s, 3H). ESIMS m/z [M+H]⁺365:1. Mp=120-122° C.

Example 25 ±trans4-[3-{[(2-methoxyphenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Example 4 (180 mg, 0.45 mmol) and Pd/C (10%, 18 mg) were suspended inEtOH (10 ml) and THF (5 ml) and stirred under an atmosphere of H₂ for 16h. The mixture was filtered through Celite and purified by columnchromatography (cyclohexane→1:1 EtOAc:cyclohexane) to give the desiredproduct as a yellow oil (70 mg, 43%). ¹H NMR (300 MHz, d₆-DMSO) δ 7.68(d, 2H), 7.30 (d, 2H), 7.22 (s, 2H), 6.80-6.74 (m, 2H), 6.63-6.51 (m,2H), 4.66 (t, 1H), 3.75 (s, 3H), 3.23 (td, 2H), 1.87 (d, 1H), 1.57 (q,1H); 1.26 (s, 3H), 0.78 (s, 3H). ESIMS m/z [M+H]⁺361.2. Mp=115-117° C.

Example 26 ±trans4-[2,2-dimethyl-3-({[3-(morpholin-4-yl)phenyl]amino}methyl)cyclopropyl]benzenesulfonamide

Intermediate BL (200 mg, 0.46 mmol) was reacted as described underGeneral Procedure F to give the title compound (156 mg, 80%) as a whitesolid after purification by column chromatography (cyclohexane→80%EtOAc/cyclohexane). ¹H NMR (300 MHz, d₆-DMSO) δ 7.87-7.78 (m, 2H),7.29-7.26 (m, 3H), 6.38 (t, 1H), 6.38-6.26 (m, 3H), 4.87 (br s, 2H),3.82 (dd, 4H), 3.30 (d, 2H), 3.11 (dd, 4H), 1.83 (d, 1H), 1.51 (q, 1H),1.30 (s, 3H), 0.86 (s, 3H). ESIMS m/z [M+H]⁺416.2.

Example 27 ±trans4-[3-{[(5-chloro-2-ethoxyphenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate BN (310 mg, 0.73 mmol) was reacted as described underGeneral Procedure F to give the title compound (218 mg, 72%) as a whitesolid after purification by column chromatography (cyclohexane 60%EtOAc/cyclohexane). ¹H NMR (300 MHz, CDCl₃) δ 7.82-7.80 (m 2H),7.31-7.26 (m 2H), 6.66-6.57 (m, 3H), 5.29 (br s, 2H), 4.38 (br s, 1H),4.03 (q, 2H), 3.35-3.21 (m, 2H), 1.85 (d, 1H), 1.54-1.32 (m, 7H), 0.87(s, ESIMS m/z [M+H]⁺409.1. Mp=122-124° C.

Example 28 ±trans4-[3-({[2-methoxy-5-(trifluoromethyl)phenyl]amino}methyl)-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate BP (220 mg, 0.49 mmol) was reacted as described underGeneral Procedure F to give the title compound (60 mg, 29%) as a whitesolid after purification by column chromatography ¹H NMR (300 MHz,d₆-DMSO) δ 7.68 (d, 2H), 7.30 (d, 2H), 7.22 (s, 2H), 6.95-6.86 (m, 2H),6.78 (s, 1H), 5.18 (br s, 1H), 3.84 (s, 3H), 3.29 (br s, 2H), 1.88 (d,1H), 1.55 (q, 1H), 1.27 (s, 3H), 0.78 (s, 3H). ESIMS m/z [M+H]⁺429.1.Mp=68-70° C.

Example 294-[(1R,3R)-3-{[(5-fluoro-2-methylphenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate BR (180 mg, 0.48 mmol) was reacted as described underGeneral Procedure F to give the title compound (95 mg, 54%) as a whitefoam. ¹H NMR (300 MHz, CDCl₃) δ 7.82 (d, 2H), 7.29 (d, 2H), 6.99 (t,1H), 6.43-6.36 (m, 2H), 4.87 (s, 2H), 3.40-3.21 (m, 2H), 2.11 (s, 3H),1.86 (d, 1H), 1.58-1.50 (m, 2H), 1.31 (s, 3H), 0.87 (s, 3H). ESIMS m/z[M+H]⁺363.1.

Example 304-[(1R,3R)-3-{[(4,5-difluoro-2-methylphenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate BT (240 mg, 0.61 mmol) was reacted as described underGeneral Procedure F to give the title compound (65 mg, 28%) as a whitefoam. ¹H NMR (300 MHz, CDCl₃) δ 7.82 (d, 2H), 7.28 (d, 2H), 6.93-6.86(m, 1H), 6.53 (br s, 1H), 4.86 (s, 2H), 3.36-3.18 (m, 2H), 2.24 (s, 3H),1.86 (d, 1H), 1.60-1.49 (m, 2H), 1.29 (s, 3H), 0.86 (s, 3H). ESIMS m/z[M+H]⁺381.1. Mp 210-212° C.

Example 314-[(1S,3S)-3-{[(5-fluoro-2-methylphenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate BV (180 mg, 0.48 mmol) was reacted as described underGeneral Procedure F to give the title compound (95 mg, 54%) as a whitesolid after purification by column chromatography (cyclohexane 1:1EtOAc/cyclohexane). ¹H NMR (300 MHz, CDCl₃) δ 7.84-7.81 (m, 2H),7.30-7.26 (m, 2H), 6.99 (t, 1H), 6.43-6.38 (m, 2H), 4.88 (br s, 2H),3.40-3.22 (m, 2H), 2.11 (s, 3H), 1.86 (d, 1H), 1.60-53 (m, 2H), 1.31 (s,3H), 0.87 (S, 3H). ESIMS m/z [M+H]⁺363.1.

Example 324-[(1S,3S)-3-{[(4,5-difluoro-2-methylphenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate BX (176 mg, 0.43 mmol) was reacted as described underGeneral Procedure F to give the title compound (100 mg, 61%) as a whitesolid after purification by column chromatography (cyclohexane 1:1EtOAc/cyclohexane). ¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, 2H), 7.28 (d,2H), 6.88 (m, 1H), 6.52-6.40 (m, 1H), 4.87 (br s, 2H), 3.34-3.18 (m,2H), 2.11 (s, 3H), 1.86 (d, 1H), 1.56-1.53 (m, 2H), 1.31 (s, 3H), 0.87(s, 3H). ESIMS m/z [M+H]⁺381.1.

Example 33 ±trans4-[3-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}methyl)-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate BZ (128 mg, 0.50 mmol) was dissolved in anhydrous THF (16ml) and the solution was degassed with N₂. MnO₂ (7 g, 80.5 mmol) wasadded in one portion and the mixture allowed to stir for 3.5 h atambient temperature. The reaction mixture was filtered through Celitedirectly onto 5-amino-2-fluorobenzotrifluoride (94 mg, 0.53 mmol) andrinsed through with anhydrous THF. The solution was stirred at ambienttemperature for 25 min after which time the mixture was concentrated invacuo and the residue taken up in 1,2-DCE (3 ml). NaBH(OAc)₃ (212 mg,1.00 mmol) was added followed by acetic acid (90 μl, 1.5 mmol) and thereaction mixture stirred at room temperature for 1.5 h, the reaction wasthen quenched with NaHCO₃ (sat. aq.) and the phases separated. Theaqueous phase was extracted with DCM (2×) and the combined organicextracts washed with brine, dried (MgSO₄) and concentrated in vacuo. Theproduct was purified by pTLC) to give the title compound as a whitesolid (95 mg, 46%). 1H NMR (300 MHz, CDCl₃) δ 7.86-7.81 (m, 2H),7.30-7.27 (m, 2H), 7.02 (t, 1H), 6.80-6.71 (m, 2H), 4.82 (s, 2H), 3.55(br, 1H), 3.34-3.20 (m, 2H), 1.85 (d, 1H), 1.60-1.44 (m, 1H), 1.28 (s,3H), 0.87 (s, 3H). ESIMS m/z [M−H]⁺415.3.

Example 34 ±trans4-[3-({[2-(difluoromethoxy)-4-fluorophenyl]amino}methyl)-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate BZ (122 mg, 0.478 mmol) and2-(difluoromethoxy)-4-fluoroaniline (89 mg, 0.502 mmol) were reacted asdescribed under Example 33 to give the title compound afterrecrystallization from EtOAc/pentane (21 mg, 11%). ¹H NMR (300 MHz,d₃MeOD) δ 7.80-7.77 (m, 2H), 7.32-7.30 (m, 2H), 6.90-6.80 (m, 3H), 6.67(t, 1H), 3.36-3.30 (m, 2H), 1.92 (d, 1H), 1.60-1.53 (m, 1H), 1.33 (s,3H), 0.84 (s, 3H). ESIMS m/z [M+H]⁺415.0.

Example 35 ±trans4-(3{[(5-tert-butyl-1,2-oxazol-3-yl)amino]methyl}-2,2-dimethylcyclopropyl)benzenesulfonamide

Intermediate BZ (116 mg, 0.454 mmol) and 3-amino-5-tert-butylisoxazole(67 mg, 0.477 mmol) were reacted as described under Example 33. Theproduct was purified by two pTLC plates (40% EtOAc/CHCl₃) one column(80% Et₂O/hexane) and then triturating with iPrOH, to remove theresidual 3-amino-5-tbutylisozazole that was contaminating the product,to give the title compound (26 mg, 15%) as a solid. ¹H NMR (300 MHz,CDCl₃) δ 7.82 (d, 2H), 7.29 (d, 2H), 5.47 (s, 1H), 4.72 (s, 2H), 3.83(br t, 1H), 3.41-3.35 (m, 2H), 1.82 (d, 1H), 1.57-1.50 (m, 1H), 1.31 (s,3H), 1.30 (s, 9H), 0.84 (s, 3H). ESIMS m/z [M−H]⁻376.3.

Example 36 ±trans4-[2,2-dimethyl-3-{[(2-methylpyridin-3-yl)amino]methyl}cyclopropyl]benzenesulfonamide

Intermediate CB (160 mg, 0.44 mmol) was reacted as described underGeneral Procedure F to give the title compound (70 mg, 46%) as a whitesolid after purification by column chromatography (cyclohexane→1:1EtOAc/cyclohexane). ¹H NMR (300 MHz, d₆-DMSO) δ 7.68-7.64 (m, 3H),7.30-7.25 (m, 4H), 7.00-6.90 (m, 2H), 5.12-5.08 (m, 1H), 3.32-3.21 (m,2H), 2.29 (s, 3H), 1.87 (d, 1H), 1.54 (q, 1H), 1.27 (s, 3H), 0.77 (s,3H). ESIMS m/z [M+H]⁺346.2. Mp=174−176° C.

Example 37 ±trans4-[3-{[(3-chloro-4-fluoro-2-methylphenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate CD (700 mg, 1.76 mmol) was reacted as described underGeneral Procedure F to give the title compound (410 mg, 59%) as a whitesolid after purification by column chromatography (cyclohexane→1:1EtOAc/cyclohexane). ¹H NMR (300 MHz, d₆-DMSO) δ 7.68 (d, 2H), 7.30 (d,2H), 7.26 (s, 2H), 7.04 (d, 1H), 6.63 (d, 1H), 4.96 (t, 1H), 3.29-3.12(m, 2H), 2.07 (s, 3H), 1.86 (d, 1H), 1.52 (q, 1H), 1.26 (s, 3H), 0.77(s, 3H). ESIMS m/z [M+H]⁺397.1. Mp=164−166° C.

Example 38 ±trans4-[3-{[(4-fluoro-2-methylphenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Example 37 (320 mg, 0.8 mmol) was reacted as described under Example 25to give the title compound (200 mg, 69%) as a white foam afterpurification by column chromatography (cyclohexane→1:1EtOAc/cyclohexane). ¹H NMR (300 MHz, d₆-DMSO) δ 7.68 (d, 2H), 7.29 (d,2H), 7.24 (s, 2H), 6.88-6.72 (m, 2H), 6.70-6.62 (m, 1H), 4.60 (br s,1H), 3.21-3.11 (m, 2H), 2.08 (s, 3H), 1.86 (d, 1H), 1.53 (q, 1H), 1.26(s, 3H), 0.77 (s, 3H). ESIMS m/z [M+H]⁺363.2.

Example 39 ±trans4-[3{[(2-ethyl-5-fluorophenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate CF (0.500 g, 1.3 mmol) was reacted as described underGeneral Procedure F to give the title compound (200 mg, 41%) as a whitesolid after purification by column chromatography (cyclohexane→1:1EtOAc/cyclohexane). ¹H NMR (300 MHz, d₆-DMSO) δ 7.67 (d, 2H), 7.31-7.25(m, 4H), 6.91 (t, 1H), 6.39 (dd, 1H), 6.26 (dt, 1H), 5.17 (br s, 1H),3.23 (m, 2H), 2.42 (q, 2H), 1.87 (d, 1H), 1.55 (q, 1H), 1.26 (s, 3H),1.09 (d, 3H), 0.76 (s, 3H). ESIMS m/z [M+H]⁺377.1.

Example 40 ±trans4-[3-({[2-fluoro-5-(trifluoromethoxy)phenyl]amino)methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate CI (200 mg, 0.45 mmol) was reacted as described underGeneral Procedure F to give the title compound (70 mg, 36%) as a clearcolourless oil after purification by column chromatography (cyclohexane1:1 EtOAc/cyclohexane). ¹H NMR (300 MHz, d₆-DMSO) δ 7.66 (d, 2H),7.30-7.25 (m, 4H), 7.09 (dd, 1H), 6.72 (dd, 1H), 6.46-6.43 (m, 1H), 5.95(br s, 1H), 3.33-3.22 (m, 2H), 1.86 (d, 1H), 1.55 (q, 1H), 1.25 (s, 3H),0.75 (s, 3H). ESIMS m/z [M+H]⁺433.1.

Example 41 ±trans4-[3-({[5-fluoro-2-(trifluoromethoxy)phenyl]amino)methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate CJ (130 mg, 0.3 mmol) was reacted as described underGeneral Procedure F to give the title compound (60 mg, 46%) as a clearcolourless oil after purification by column chromatography (cyclohexane1:1 EtOAc/cyclohexane). ¹H NMR (300 MHz, d₅-DMSO) δ 7.66 (d, 2H),7.29-7.24 (m, 1H), 7.17-7.11 (m, 1H), 6.69 (dd, 1H), 6.32 (dt, 1H), 5.96(br s, 1H), 3.35-3.20 (m, 2H), 1.86 (d, 1H), 1.56 (q, 1H), 1.24 (s, 3H),0.74 (s, 3H). ESIMS m/z [M+H]⁺433.1.

Example 42 ±trans4-(3{[(2-methoxypyridin-3-yl)amino]methyl}-2,2-dimethylcyclopropyl)benzenesulfonamide

Intermediate CK (135 mg, 0.53 mmol) was reacted as described underGeneral Procedure I to furnish the title compound as a white solid (30mg, 47%) after purification by column chromatography (100%cyclohexane→50% EtOAc/cyclohexane). ¹H NMR (300 MHz, d₆-DMSO) δ 7.67 (d,2H), 7.35-7.24 (m, 5H), 6.86-6.74 (m, 2H), 5.03-4.99 (m, 1H), 3.85 (s,3H), 3.25-3.19 (m, 2H), 1.87 (d, 1H), 1.57 (q, 1H), 1.25 (s, 3H), 0.77(s, 3H). ESIMS m/z [M+H]⁺362.2. Mp=98-100° C.

Example 43 ±trans4′-[3-{[(5-chloro-2-methoxyphenyl)amino]methyl}-2,2-dimethylcyclopropyl]biphenyl-2-ol

Intermediate CP (135 mg, 0.32 mmol) was reacted as described underGeneral Procedure F to give the title compound as a white solid (102 mg,78%) after purification by column chromatography (cyclohexane→60%cyclohexane/EtOAc). ¹H NMR (300 MHz, CDCl₃) δ 7.40-7.36 (m, 2H),7.32-7.22 (m, 5H), 7.00-6.97 (m, 2H), 6.66 (s, 3H), 5.26 (br s, 1H),3.84 (s, 3H), 3.29 (dq, 2H), 1.83 (d, 1H), 1.54-1.43 (m, 1H), 1.31 (s,3H), 0.93 (s, 3H). ESIMS m/z [M+H]⁺408.1.

Example 44 ±trans4-[3-{[(2-ethoxyphenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Example 27 (98 mg, 0.24 mmol) was reacted as described under Example 25to furnish the title compound as a white solid (50 mg, 56%) afterpurification by column chromatography. ¹H NMR (300 MHz, d₆-DMSO) δ 7.70(d, 2H), 7.32 (d, 2H), 7.26 (s, 2H), 6.81-6.75 (m, 2H), 6.65 (d, 1H),6.54 (t, 1H), 4.63 (m, 1H), 4.01 (q, 2H), 3.27-3.23 (m, 2H), 1.90 (d,1H), 1.58 (q, 1H), 1.32 (t, 3H), 1.29 (s, 3H), 0.80 (s, 3H). ESIMS m/z[M+H]⁺375.1. Mp=46-48° C.

Example 45 ±trans4-[3-({[5-chloro-2-(trifluoromethyl)phenyl]amino}methyl)-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate CR (150 mg, 0.36 mmol) was reacted as described underGeneral Procedure F to furnish the title compound as a white solid (50mg, 32%) after purification by chromatography. ¹H NMR (300 MHz, d₆-DMSO)δ 7.67 (d, 2H), 7.40 (d, 1H), 7.28 (d, 2H), 7.23 (s, 2H), 6.95 (s, 1H),6.68 (d, 1H), 5.53 (m, 1H), 3.40-3.36 (m, 2H), 1.90 (d, 1H), 1.54 (q,1H), 1.26 (s, 3H), 0.76 (s, 3H). ESIMS m/z [M+H]⁺433.0. Mp=124-126° C.

Example 46 ±transN-(4-[3-{[(5-chloro-2-methoxyphenyl)amino]methyl}-2,2-dimethylcyclopropyl]phenyl)methanesulfonamide

Intermediate CS (150 mg, 0.35 mmol) was reacted as described underGeneral Procedure F to furnish the title compound as a white solid (137mg, 94%) after purification by chromatography (100% cyclohexane 60%EtOAc/cyclohexane). ¹H NMR (300 MHz, CDCl₃) δ 7.13 (s, 4H), 6.73-6.69(m, 2H), 6.48 (br s, 1H), 3.84 (s, 3H), 3.35-3.25 (m, 2H), 2.99 (s, 3H),2.00 (s, 2H), 1.75 (d, 1H), 1.46-1.42 (m, 1H), 1.25 (s, 3H), 0.84 (s,3H). ESIMS m/z [M+H]⁺409.1.

Example 47 Enantiomer A of transN-{4-[3-{[(5-chloro-2-methoxyphenyl)amino]methyl}-2,2-dimethylcyclopropyl]phenyl}methanesulfonamideExample 48 Enantiomer B of transN-{4-[3-{[(5-chloro-2-methoxyphenyl)amino]methyl}-2,2-dimethylcyclopropyl]phenyl}methanesulfonamide

The trans-racemate Example 46 was separated into individual, enantiomersby preparative HPLC (Chiralpak OJ-H (20×250) mm, 5 μm, 10 mL/min,n-Hexane:Ethanol, 1:1, Inj. V. 200 μL 10 mg/injection)), Example 47 isthe first eluting isomer, Rt=17.45 min, 100% ee, and Example 48 is thesecond eluting isomer, Rt=26.03 min, 100% ee.

Example 49 ±trans4-[2-{[(3-methylpyridin-2-yl)amino]methyl}spiro[2.4]hept-1-yl]benzenesulfonamide

Intermediate CV (140 mg, 0.50 mmol) and 3-methyl-2-pyridinamine (54 mg,0.05 mmol) were reacted as described under General Procedure I tofurnish the title compound as a white solid (18 mg, 10%) afterpurification by column chromatography followed by p-TLC. ¹H NMR (300MHz, d₆-DMSO) δ 7.86 (d, 1H), 7.67 (d, 2H), 7.21-7.17 (m, 5H), 6.41 (dd,1H), 5.83 (t, 1H), 3.51-3.35 (m, 2H), 2.01 (s, 3H), 1.96-1.89 (m, 3H),1.83-1.37 (m, 6H), 1.12-1.00 (m, 1H). ESIMS m/z [M+H]⁺372.2. Mp=82-84°C.

Example 504-[(1S,3S)-3-({[2-(difluoromethoxy)-4-fluorophenyl]amino)methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate CY (130 mg, 0.51 mmol) and2-(difluoromethoxy)-4-fluoroaniline (95 mg, 0.54 mmol) were reacted asdescribed for Example 33 to furnish the title compound as a pale pinkoil (85 mg, 40%) following purification by pTLC (30% EtOAc/hexane). ¹HNMR (300 MHz, CDCl₃) δ 7.83 (d, 2H), 7.28 (d,), 6.89-6.82 (m, 2H),6.69-5.20 (m, 2H), 4.81 (s, 2H), 4.03 (br s, 1H), 3.35 (dd, 1H), 3.21(dd, 1H), 1.84 (d, 1H), 1.52-1.46 (m, 1H), 1.31 (s, 3H), 1.86 (s, 3H).ESIMS m/z [M+H]⁺415.0.

Example 514-[(1R,3R)-3-({[2-(difluoromethoxy)-4-fluorophenyl]amino}methyl)-2,2-dimethylcyclopropyl]benzenesulfonamide

Intermediate DB (130 mg, 0.51 mmol) and2-(difluoromethoxy)-4-fluoroaniline (95 mg, 0.54 mmol) were reacted asdescribed under Example 33 to furnish the title compound as a pale pinkoil (97 mg, 46%) following purification by pTLC (35% EtOAc/hexane). ¹HNMR (300 MHz, CDCl₃) δ 7.83 (d, 2H), 7.28 (d, 2H), 6.90-6.83 (m, 2H),6.69-5.20 (m, 2H), 4.76 (s, 2H), 4.03 (br s, 1H), 3.35 (dd, 1H), 3.21(dd, 1H), 1.84 (d, 1H), 1.53-1.46 (m, 1H) 1.32 (s, 3H), 1.86 (s, 3H).ESIMS m/z [M+H]⁺415.0

Example 524-[(1S,2S)-2-({[5-fluoro-2-(trifluoromethoxy)phenyl]amino}methyl)cyclopropyl]benzenesulfonamide

Intermediate DD (190 mg, 0.45 mmol) was reacted as described underGeneral Procedure F to furnish the title compound as a white solid (17mg, 9%) after purification by column chromatography. ¹H NMR (300 MHz,d₆-DMSO) δ 7.64 (d, 2H), 7.20-7.11 (m, 5H), 6.66 (dd, 1H), 6.32 (td,),6.11-6.08 (m, 1H), 3.19 (t, 2H), 1.98-1.92 (m, 1H), 1.43 (m, 1H)1.03-0.97 (m, 2H). ESIMS m/z [M+H]⁺405.1. Mp=115-118° C.

Example 534-[(1R,2R)-2-({[5-fluoro-2-(trifluoromethoxy)phenyl]amino}methyl)cyclopropyl]benzenesulfonamide

Intermediate DF (120 mg, 0.29 mmol) was reacted as described underGeneral Procedure F to furnish the title compound as a white solid (55mg, 47%) after purification by column chromatography. ¹H NMR (300 MHz,d₆-DMSO) δ 7.64 (d, 2H), 7.20-7.11 (m, 5H), 6.66 (dd, 1H), 6.32 (td,1H), 6.11-6.08 (m, 1H), 3.19 (t, 2H), 1.98-1.92 (m, 1H), 1.43 (m, 1H)1.03-0.97 (m, 2H). ESIMS m/z [M+H]⁺405.1. Mp=115-118° C.

Example 54 ±trans4-{[-2{[(5-chloro-2-methoxyphenyl)amino]methyl}cyclopropyl]methyl}benzenesulfonamide

Intermediate DI (1.0 g, 3.5 mmol) was reacted as described under GeneralProcedure F to furnish the title compound as a white solid (500 mg, 53%)after purification by column chromatography ¹H NMR (300 MHz, d₆-DMSO) δ7.72 (d, 2H), 7.45 (d, 2H), 7.23 (s, 2H), 6.75 (d, 1H), 6.53-6.50 (m,2H), 4.80-4.72 (m, 1H), 3.74 (s, 3H), 3.17-3.08 (m, 2H), 2.85-2.26 (m,2H), 1.26-1.09 (m, 2H), 0.77-0.71 (m, 1H), 0.26-0.18 (m, 1H) ESIMS m/z[M+H]⁺381.1. Mp=126-128° C.

Example 55 ±trans4-[3-{[(5-chloro-2-methoxyphenyl)amino]methyl}-2,2-dimethylcyclopropyl]N-hydroxybenzenesulfonamide

Intermediate DK (49 mg, 0.12 mmol) was reacted as described underGeneral Procedure F to furnish the title compound (12 mg, 95%) afterpurification by pTLC (40% EtOAc/hexane). ¹H NMR (300 MHz, CDCl₃) δ7.87-7.83 (m, 2H), 7.36-7.32 (m, 2H), 6.71-6.59 (m, 4H), 6.22 (brs, 1H),3.83 (s, 3H), 3.30-3.25 (m, 2H), 1.86 (d, 1H), 1.67 (brs, 1H), 1.54 (q,1H), 1.33 (s, 3H), 0.88 (s, 3H). ESIMS m/z [M+H]⁻411.0.

Example 56 ±trans4-[3-{[(5-chloro-2-methoxyphenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonohydrazide

Intermediate DL (0.200 g, 0.47 mmol) was reacted as described underGeneral Procedure F to furnish the title compound as a crystalline solid(36 mg, 19%) after purification by column chromatography (50%EtOAc/hexane) followed by recrystallisation from Et₂O. ¹H NMR (300 MHz,CDCl₃) δ 7.83-7.79 (m, 2H), 7.35-7.32 (m, 2H), 6.68-6.58 (m, 3H), 5.57(br s, 1H), 4.34 (br s, 1H), 3.83 (s, 3H), 3.62 (br s, 2H), 3.35-3.20(m, 2H), 1.86 (d, 1H), 1.53 (q, 1H), 1.33 (s, 3H), 0.88 (s, 3H). ESIMSm/z [M+H]⁺410.0.

Example 57 Enantiomer A of trans4-[-3-{[(4-fluoro-2-methylphenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamideExample 58 Enantiomer B of trans4-[-3-{[(4-fluoro-2-methylphenyl)amino]methyl}-2,2-dimethylcyclopropyl]benzenesulfonamide

The trans-racemate Example 38 was separated into individual enantiomersby SFC (Lux cellulose-3 (250×4.6) mm, 5 m, CO₂/Methanol 7:3, 3 mLmin⁻¹,35° C., 100 bar), Example 57 is the first eluting isomer, Rt=5.58 min,100% ee, and Example 58 is the second eluting isomer, Rt=7.20 min, 100%ee.

Example 59 ±transN-[4-(3-{[(5-chloro-2-methoxyphenyl)amino]methyl}-2,2-dimethylcyclopropyl)phenyl]sulfuricdiamide

A small Schlenk flask was charged with K₃PO₄ (1.91 g, 9.0 mmol) under adry atmosphere of nitrogen (drying tube fitted), 1,4-dioxane (33 ml) wasadded followed by ^(t)BuXPhos (104 mg, 0.245 mmol) and Pd₂(dba)₃ (75 mg,0.0818 mmol). The mixture was freeze-pump-thaw degassed three times.Intermediate DO (3.23 g, 8.18 mmol) and sulfamide (944 mg, 9.82 mmol)were added and the reaction mixture stirred under a nitrogen atmosphereat room temperature for 30 minutes before heating to 80° C. overnight.The reaction mixture was cooled to room temperature, diluted with EtOAcand washed with HCl (1 M aq. 2×), dried (MgSO₄) and concentrated invacuo. The product was purified by pTLC (40% EtOAc/hexane) to yield 111mg (3%) of the title compound. ¹H NMR (300 MHz, CDCl₃) δ 7.15 (s, 4H),6.67-6.57 (m, 3H), 6.38 (br s, 1H), 4.66 (br s, 2H), 4.35 (br s, 1H),3.83 (s, 3H), 3.30-3.18 (m 2H), 1.76 (d, 1H), 1.39 (q, 1H), 1.29 (s,3H), 0.88 (s, 3H). ESIMS m/z [M+H]⁺410.0.

Example 60 Enantiomer A of transN-[4-(3-{[(5-chloro-2-methoxyphenyl)amino]methyl}-2,2-dimethylcyclopropyl)phenyl]sulfuricdiamide Example 61 Enantiomer B of transN-[4-(3{[(5-chloro-2-methoxyphenyl)amino]methyl}-2,2-dimethylcyclopropyl)phenyl]sulfuricdiamide

The trans-racemate Example 59 was separated into individual enantiomersby chiral HPLC (Chiralcel OJ-H (250×4.6) mm, 5 μm, mobile phasen-hexane: EtOH 30:70, 1 mLmin⁻¹), Example 60 is the first elutingisomer, Rt=11.9 min, 100% ee, and Example 61 is the second elutingisomer, Rt=19.3 min, 98.14% ee.

Example 62 trans4-(3-{[(2,2-difluorocyclohexyl)amino]methyl}-2,2-dimethylcyclopropyl)benzenesulfonamide

Intermediate DQ (0.415 g) was reacted as described under GeneralProcedure F to furnish the title compound (27 mg) as a colourless solid,as a pair of diastereomers, after purification by column chromatography(60% EtOAc/hexane) followed by pTLC (50% EtOAc/CHCl₃) andrecrystalisation from EtOAc and hexane. ¹H NMR (300 MHz, CDCl₃) δ7.83-7.79 (m, 2H), 7.30-7.26 (m, 2H), 4.74 (brs, 2H), 3.03-2.78 (m, 3H),2.21-2.13 (m, 1H), 2.00-1.89 (m, 1H), 1.80-1.26 (m, 11H), 0.82-0.81 (m,3H). ESIMS m/z [M+H]⁺373.3.

Pharmacology

Example P1: CellLux Fluorescence Assay to Detect Agonists and PositiveAllosteric Modulators of α7 nAChR

Compounds were screened for positive allosteric modulation (PAM) of α7nACh receptors on the CellLux (Perkin Elmer) with a fluorescence-basedcalcium assay. Activation of the α7 nAChR by endogenous Uganda, resultsin a calcium flux which can be measured using ion specific fluorescentdyes. The fluorescence assay was run in a high throughput format on theCellLux, an automated fluorescent plate reader with liquid handlingcapabilities. The assay measured intracellular calcium changes in aGH4C1 cell line stably expressing α7 nAChRs, when treated with compoundsthat positively modulated an ACh-induced response. Compound was addedfirst to identify any agonist activity followed by ACh addition (EC20concentration) to measure PAM activity.

Prior to assay, α7/GH4C1 cells were seeded in 96-well plates(PDL-coated) and incubated for 48 hours at 33° C. in 5% CO₂. The cellswere grown in F10Ham media plus 15% horse serum, 2.5% FCS, 2 mMpenicillin, 2 mM streptomycin, 2 mM glutamine and 10 mM Hepes(Invitrogen). 0.5 mM sodium butyrate, a growth arrestor, was added tothe cells during the incubation period to increase expression of α7nAChR. On the day of assessment, the media was removed and the cellswere washed with HBSS buffer (1 mM CaCl₂, 0.5 mM MgCl₂, 0.4 mM MgSO₄, 5mM KCL, 0.4 mM KHPO₄, 4 mM NaHCO₃, 137 mM NaCl, 0.3 mM Na₂HPO₄, 5.5 mMglucose and 1M Hopes, pH7.4) and then Fluo-4 Direct Calcium dye(Molecular Probes; Excitation: 495 nm; Emission: 516 nm) was added. Thecells were incubated with dye for 30 minutes at 33° C. Compoundaddition, ACh addition and fluorescence measurements were performed onthe CellLux.

The CellLux recorded fluorescent responses at 5 second intervalsstarting with a 10 second baseline reading, the compound was then addedand the response was read for 1 minute. ACh was then added and theresponse read for a further 2 minutes, a total of 4 minutes. Thisprotocol detects agonist and PAM activity of compounds at the α7 nAChR.

Compounds were tested at 6 doses, in triplicate, 0.03, 0.1, 0.3, 1, 3and 10 uM. Working stocks were prepared in DMSO from 10 mM DMSO stocksand then 10× starting stocks were prepared by diluting 1:100 in HBSSbuffer (0.1% DMSO final). A 10× starting dilution of an EC20concentration of ACh was prepared in HBSS buffer (0.1% DMSO final).Negative control was HBSS buffer (0.1% DMSO final).

Data was analysed by calculating % potentiation of compound compared tothe ACh control response, where ACh potentiation was set at 0%.Peak/base values were calculated for each compound concentration (n=3)using AssayPro program (CellLux) and these values were used to determine% potentiation based on the ACh control peak/base value. Compounds wereidentified as active if they showed statistically significantpotentiation of the control ACh response. For active compounds %potentiation values were used to calculate compound EC50 values inGraphPad Prism 4.

Example P2: Electrophysiology Protocol to Detect α7 nAChR PositiveAllosteric Modulator Activity

Compound Preparation:

Tested compounds were prepared by serial dilutions of 10 mM stocksolution in DMSO to concentrations of the compound 1000 times higherthan its final concentration. The DMSO stock solutions were then diluted1:100 in the recording buffer bringing DMSO concentration to 1%. Theseintermediate solutions were further diluted 10 times with buffer toobtain final concentrations and lower DMSO concentration to 0.1%.

Acetylcholine chloride (ACh) purchased from Sigma-Aldrich(Sigma-Aldrich, St Louis, Mo.) was used as an α7 nAChR agonist at aconcentration corresponding to EC₂₀ measured by peak current.

Calculation of the Effect on α7 nAChR-Mediated Currents:

The effect of tested compounds on ACh-evoked currents was calculated bythe following formula:

${{Effect}\mspace{14mu} (\%)} = {\left( {\left( \frac{I_{compound}}{I_{control}} \right) - 1} \right) \times 100}$

Therefore, zero indicates no effect, negative numbers correspond topercentage of inhibition and positive numbers to percentage ofpotentiation relative to control ACh responses at EC₂₀. The formula wasused for calculations of effects on both peak current and area undercurve (AUC).

Example P2.1; Automated Planar Patch-Clamp:

Compounds of the invention may be evaluated by electrophysiology using aPatchliner® (Nanion Technologies GmbH, Germany), an automated planarpatch-clamp platform of medium throughput was used as a first step inelectrophysiological assessment of α7 nAChR positive allostericmodulators (PAMs).

Briefly, intracellular (KCl˜50 mM, NaCl-10 mM, KF-60 mM, EGTA-20 mM,HEPES-10 mM, pH-7.2, 285 mOsmol) and extracellular (NaCl-140 mM, KCl-4mM, CaCl₂-2 mM, MgCl₂-1 mM, HEPES-10 mM, D-Glucose-5 mM, pH-7.4, 298mOsmol) solutions were automatically pipetted onto NPC-16 chip (mediumresistance˜2.5-2.6 MΩ). Suspension of GH4C1 cells expressing rat α7nAChRs was introduced in 4 wells of a medium resistance chip and suctionwas applied to attract cells in the holes. The extracellular solutionwas subsequently exchanged to high calcium solution (NaCl-80 mM, KCl-3mM, CaCl₂-45 mM, HEPES-10 mM, pH-7.4, 298 mOsmol) followed by gigaohmseal formation and obtaining whole-cell configuration. The rest ofprotocol was carried out in the high-calcium recording solution. Holdingpotential was −70 mV throughout the protocol. A control response to 60or 100 μM of ACh was obtained first. Next, a cell was pre-incubated withcompound of interest at 3 μM for ˜30 s after which the compound wasco-applied with acetylcholine.

Amplitude of the responses was measured in HEKA Patchmaster software(HEKA Elektronik, Germany) and percentage of potentiation calculated.Recording was repeated unless a minimum of two replicates had beenobtained per compound.

Example P2.2; Manual Patch Clamp:

Compound of the invention may be evaluated by electrophysiology on amanual patch-clamp setup using a fast-application add-on Dynaflow®(Cellectricon AB, Sweden). The fast application system allows resolutionof true peak amplitudes, which otherwise would be affected by rapidreceptor desensitization, and thus greatly improves measurementprecision with fast ligand gated channels such as α7 nAChR.

GH4C1 cells expressing rat α7 nAChRs were patch-clamped in the recordingchamber of 16-channel re-usable Dynaflow® ReSolve chips using EPC10 USBamplifier (HEKA Elektronik, Germany). Extracellular solution containedNaCl-137 mM, KCl-5 mM, CaCl₂-2.5 mM, MgCl₂-1 mM, HEPES-10 mM,D-Glucose-10 mM, pH-7.4. Thin wall borosilicate glass electrodes(Harvard Apparatus) were pulled to a resistance of 2-4 MΩ when filledwith intracellular solution (K*-gluconate-120 mM, KCl-5 mM, HEPES-10 mM,EGTA-10 mM, MgCl₂-1 mM, ATP-2 mM, pH-7.2). Cells were held at −70 mV.Cells with series resistance below 15 MΩ were kept and 40% compensationwas utilized routinely.

The recording protocol consisted of obtaining of two control AChresponses (EC₂₀, peak, 250 ms pulse) prior to 30 s pre-incubation with atested compound (3 μM) followed by 250 ms co-application of 3 μMcompound plus EC₂₀ ACh. Dose-responses for selected compounds wereobtained by a continuous compound application of increasingconcentrations alternated with co-applications of compound plus EC₂₀ AChevery 30 seconds.

Current amplitudes along with net charge carried (area under curve, AUC)were measured in Patchmaster software (HEKA Elektronik, Germany) andpercentage of peak current and AUC potentiation by test compounds wascalculated using the above mentioned formula. Dose-responses forselected compounds were fitted and plotted in Prism4/5 (GraphPadSoftware, Inc., Calif.).

Example P3: Animal Model of Cognitive Enhancement—T-Maze ContinuousAlternation Task (T-CAT)-Mouse

The cognition enhancing properties of the compounds in the inventionwere evaluated in an animal model where cognitive impairment ispharmacologically induced by Scopolamine, a muscarinic receptorantagonist which is used as a standard/reference drug for inducingcognitive deficits in healthy humans and animals.

The T-maze Continuous Alternation Task (T-CAT) measures spontaneousalternation, which is the innate tendency of mice to alternate freechoices in a T-maze over a series of successive runs. This sequentialprocedure relies on working memory and is sensitive to variouspharmacological manipulations affecting memory processes.

The T-maze apparatus is made of gray Plexiglas with a main stem (55 cmlong×10 cm wide×25 cm high) and two arms (30 cm long×10 cm wide×25 cmhigh) positioned at 90 degree angle relative to the main stem. A startbox (15 cm long×10 cm wide) is separated from the main stem by a slidingdoor. Sliding doors are also provided to close specific arms during theforced-choice alternation task.

The experimental protocol consists of one single session, which startswith 1 “forced-choice” trial, followed by 14 “free-choice” trials. Inthe first “forced-choice” trial, the animal is confined for 5 s in thestart arm and then it is released while either the left or right goalarm is blocked by a sliding door. The animal will negotiate the maze,eventually enter the open goal arm, and return to the start position.Immediately after the return to the start position, the left or rightgoal door is opened and the animal is allowed to choose freely betweenthe left and right goal arm (“free choice” trials). The animal isconsidered to have entered an arm when it places four paws in the arm. Asession is terminated and the animal is removed from the maze as soon as14 free-choice trials have been performed or 10 minutes have elapsed,whichever event occurs first. The percentage of alternation over the 14free-choice trials is determined for each mouse and is used as an indexof working memory performance. This percentage is defined as entry in adifferent arm of the T-maze over successive visits (i.e.,left-right-left-right, etc).

Scopolamine administered 20 minutes prior the initiation of the T-mazesession is used to induce disruption in the spontaneous alternation ofmice. Test compounds are administered 60 minutes prior the start of theT-maze session in order to evaluate their ability to reverse thescopolamine effect.

The apparatus is cleaned between each animal using alcohol)(70°. Urineand faeces are removed from the maze. During the trials, animal handlingand the visibility of the operator are minimized as much as possible.

Example P4: Animal Model of Cognitive Enhancement-Novel ObjectRecognition Test-Rat

The object recognition task is used to assess the short term memory inrats and is based on the natural tendency of rats to preferentiallyexplore a novel versus a familiar object, which requires memory of thefamiliar object.

Equipment

The apparatus consists of an open acrylic glass cage (101 cm×101 cm;with 45 cm walls) within which animals can move freely. The two objectsused in the assay are a metallic ball and a black box. The animal'sapproaches to the objects are recorded by an observer using stopwatch.

Methods Step 1—Habituation:

Twenty four hours before the first trial, animals are allowed tohabituate to the open-field apparatus for 15 minutes

Step 2—Acquisition Trial:

One object (Object A) is placed in a particular corner of the centralsquare.

Animals are randomly exposed to the experimental situation for 10minutes. Their explorative approaches to the object are recorded.Animals which don't display locomotor activity (total immobility) or donot explore the object are excluded.

Step 3—Retention Trial:

The test for retention is performed 30 minutes after the acquisitiontrial. Object A and the second object (Object B) are placed on adjacentcorners of the central square. Each animal is exposed to theexperimental situation for 10 minutes while exploratory approachestowards the two objects are recorded.

Step 4—Recognition Index:

For each animal, the time taken to explore object A (tA) and object B(tB) are recorded and the recognition index (RI) determined using theformula: RI=tB/(tA+tB)×100 where, tB is the time spent exploring ObjectB and tA is the time spent exploring object A, values which arecollected during the retention trial. In addition, the results are alsoexpressed as the difference between exploration time of the new and thefamiliar objects.

Drugs and Treatment Groups:

Each animal receives test substances or vehicle treatments at timesshown below:

Groups Treatment Time Control vehicle (per os) 1 hour before theacquisition trial Scopolamine 0.6 mg/kg (i.p.) 20 min before theacquisition trial Test Compounds (dose) mg/kg (per os) 1 hour before theacquisition trial

Data Analysis

One-way analysis of variance (ANOVA) followed by Fisher's ProtectedLeast Significant Difference is used to compare pairs of group means.p≦0.05 are deemed significant.

Biological Data

Compounds shown in Table 1 were evaluated by automated planar patchclamp on the Patchliner® as described in Example P2.1. Table 1 shows the% effect on peak potentiation caused by 3 μM of compounds of theinvention in the presence of acetylcholine. The compounds are designatedeither as Type I or Type II modulators based on the electrophysiologytrace. Type 1 predominately affects the peak current. Type II modulatorsaffect the peak current and also delay the desensitization of thereceptor.

TABLE 1 Example Peak potentiation at 3 μM compound Type I or Type II 15520% II 2 2999% II 3  969% I 4 7909% II 5 2566% II 6  506% I 7  134% I8 9894% II 9 2101% II 10 2996% II 11  15% II 12  401% I 13 3124% II 141104% II 15  413% I 16  236% I 17 2862% I 18 2857% I 19  762% I 20 1072%I 21 14696%  II 22 12311%  II 23 8940% II 24  901% II 25 3409% II 26 455% II 27 4068% I 28 8167% II 29  456% I 30  419% I 31 17430%  II 328931% II 33 1501% II 34 3661% II 35  57% II 36  125% II 37 9231% II 388655% II 39 5276% II 40  309% II 41 2437% I 42 2418% II 43  100% I 441813% I 45 2417% I 46  783% I 47  867% I 49 1450% II 50 8167% II 51 171% I 52 3068% II 53 4388% II 54  574% I 55  724% I 56  131% I 57 473% I 58 17581%  II 59 3158% I 62  38% II

Compounds shown in Table 2 showed a significant effect in the mouseT-maze Continuous Alternation Task as described in Example P3. Thecompounds were dosed orally at 10 mg/kg.

TABLE 2 Example T-maze % control at 10 mg/kg 3 62 13 80 17 100 20 100 21100 30 70 50 77 51 81

1) A compound of formula (I) or salt thereof:

wherein R₁ is selected from optionally substituted aryl, optionallysubstituted benzyl, optionally substituted heteroaryl, or optionallysubstituted heterocyclyl; R₂ is selected from hydrogen, C₁-C₄ alkyl, F,Cl, CN, phenyl or C₁-C₄ haloalkyl; R₃ is selected from hydrogen, C₁-C₄alkyl, F, Cl, CN, or C₁-C₄ haloalkyl; or R₂ and R₃ together form C₄-C₉cycloalkyl or C₄-C₉ cycloalkenyl; R₄ is selected from optionallysubstituted heteroaryl, optionally substituted heterocyclyl, oroptionally substituted aryl; R₅ is selected from hydrogen or C₁-C₄alkyl; R₆-R₈ are independently selected from halogen or hydrogen; and nis 1-3, wherein when R₂ and R₃ are hydrogen, and n is 1, R₁ is not (1)phenyl or phenyl substituted with cyclohexyl, heterocyclyl, F or OCH₃;or (2) optionally substituted heteroaryl. 2) A compound according toclaim 1 or a salt thereof wherein R₁ is selected from: optionallysubstituted benzyl; a optionally substituted aryl; optionallysubstituted heteroaryl; or optionally substituted heterocyclyl. 3.(canceled) 4) A compound according to claim 1 represented by formula(Ia) or a salt thereof:

wherein R_(1a) is selected from the group consisting of optionallysubstituted lower alkyl, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, —P═O(OH)(NH₂), —C(O)NR′R′, —NR′S(O)₂NR′R′,—NR′—S(O)₂R′, —NR′C(O)R′, —S(O)₂—NR′R′ and —NR′R′ (where each R′ isindependently selected from hydrogen, lower alkyl, C₃-C₇ cycloalkyl,heterocyclyl, heteroaryl, —OH, or NH₂), —S(O)R″ (where R″ is loweralkyl, or cycloalkyl), and —S(O)₂R′″ (where R′″ is lower alkyl, orcycloalkyl); each R_(1b) is independently —H, cyano, halo, nitro,optionally substituted lower alkyl, optionally substituted aryl,optionally substituted aryloxy, optionally substituted arylalkyl,optionally substituted heteroaryl, optionally substituted heterocyclyl,optionally substituted C₃₋₇ cycloalkyl, —P═O(OH)(NH₂), —OR, —C(O)R,—C(O)OR, —OC(O)R (where R is selected from hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, andoptionally substituted aryl), —C(O)NR′R″, —NR′C(O)R″, —S(O)₂—NR′R″ and—NR′R″ (where R′ and R″ are independently selected from hydrogen orlower alkyl), —S(O)R′″ (where R′″ is lower alkyl, or cycloalkyl),—S(O)₂R′″ (where R′″ is lower alkyl, cycloalkyl or OH), or any twoadjacent R_(1b) or R_(1a) and R_(1b) together form heterocyclyl orheteroaryl; z is 4; R₂ is selected from hydrogen, C₁₋₄ alkyl, F, Cl, CN,phenyl or C₁-C₄ haloalkyl; R₃ is selected from hydrogen, C₁-C₄ alkyl, F,Cl, CN, or C₁-C₄ haloalkyl; or R₂ and R₃ together form C₄-C₉ cycloalkylor C₄-C₉ cycloalkenyl; R₄ is selected from optionally substitutedheteroaryl, optionally substituted heterocyclyl, or optionallysubstituted aryl; R₅ is selected from hydrogen or C₁-C₄ alkyl; R₆-R₈ areindependently selected from halogen or hydrogen; and n is 1-3. 5-8.(canceled) 9) A compound according to claim 1 represented by formula(Ib) or a salt thereof:

wherein R₁ is selected from optionally substituted aryl, optionallysubstituted benzyl, optionally substituted heteroaryl or optionallysubstituted heterocyclyl; R₂ and R₃ together form C₄-C₉ cycloalkyl; R₄is selected from optionally substituted heteroaryl, optionallysubstituted heterocyclyl, or optionally substituted aryl; R₅ is selectedfrom hydrogen or C₁-C₄ alkyl; R₆-R₈ are independently selected fromhalogen or hydrogen; and n is 1-3.
 10. (canceled) 11) A compoundaccording to claim 9 or a salt thereof wherein R₁ is a phenyl groupsubstituted with R_(1a), wherein R_(1a) is selected from the groupconsisting of optionally substituted lower alkyl, optionally substitutedaryl, optionally substituted aryloxy, optionally substituted heteroaryl,optionally substituted heterocyclyl, —P═O(OH)(NH₂), —C(O)NR′R′,—NR′S(O)₂NR′R′, —NR′—S(O)₂R′, —NR′C(O)R′, —S(O)₂—NR′R′ and —NR′R′ (whereeach R′ is independently selected from hydrogen, lower alkyl, C₃-C₇cycloalkyl, heterocyclyl, heteroaryl, —OH, or NH₂), —S(O)R″ (where R″ islower alkyl, or cycloalkyl), and —S(O)₂R′″ (where R′″ is lower alkyl, orcycloalkyl).
 12. (canceled) 13) A compound according to claim 1represented by formula (Ic) or a salt thereof:

wherein R₁ is selected from optionally substituted aryl, optionallysubstituted benzyl, optionally substituted heteroaryl or optionallysubstituted heterocyclyl; R₂ and R₃ each independently represent C₁-C₃alkyl; R₄ is selected from optionally substituted heteroaryl, optionallysubstituted heterocyclyl, or optionally substituted aryl; R₅ is selectedfrom hydrogen or C₁-C₄ alkyl; R₆-R₈ are independently selected fromhalogen or hydrogen; and n is 1-3. 14-16. (canceled) 17) A compoundaccording to claim 1 represented by formula (I′), or a salt thereof:

wherein R₁ is selected from optionally substituted aryl, optionallysubstituted benzyl, optionally substituted heteroaryl, or optionallysubstituted heterocyclyl; R₂ is selected from C₁-C₄ alkyl, F, Cl, phenylor C₁-C₄ haloalkyl; R₃ is selected from hydrogen, C₁-C₄ alkyl, F, Cl,CN, or C₁-C₄ haloalkyl; or R₂ and R₃ together form C₄-C₈ cycloalkyl orC₄-C₉ cycloalkenyl; R₄ is selected from optionally substitutedheteroaryl, optionally substituted heterocyclyl, or optionallysubstituted aryl; R₅ is selected from hydrogen or C₁-C₄ alkyl; and n is1-3. 18-21. (canceled) 22) A compound according to claim 1 wherein R₄ isan optionally substituted heteroaryl or optionally substituted aryl andR⁵ is —H or —CH₃.
 23. (canceled) 24) A compound according to claim 22wherein R₄ is selected from:

(a) wherein Hal is a halogen; p is 0, 1 or 2; and each R₉ isindependently selected from halogen, CN, NO₂, haloalkyl, aryl,heteroaryl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, C₁₋₃ alkyl, or CO₂R′ (where R′is a lower alkyl or H); or

(b) wherein Hal is a halogen; p is 0, 1 or 2; and each R₉ isindependently selected from halogen, CN, NO₂, haloalkyl, aryl,heteroaryl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, C₁₋₃ alkyl, or CO₂R′ (where R′is a lower alkyl or H); or (c) a heteroaryl substituted from 1 to 3times from a group selected from C₁-C₃ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₃ haloalkoxy, —OH, phenyl, benzyl,phenoxy, benzyloxy, benzoyl, —NH₂, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, —CN,—NO₂, mercapto, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, CO₂H, —S(O)R′″(where R′″ is lower alkyl or cycloalkyl) and —S(O)₂R′″ (where R′″ islower alkyl, cycloalkyl or OH). 25) A compound according to claim 1represented by formula (Ia′), or a salt thereof:

wherein each R_(1a) is independently selected from the group consistingof optionally substituted aryl, optionally substituted aryloxy,optionally substituted heteroaryl, optionally substituted heterocyclyl,—P═O(OH)(NH₂), —C(O)NR′R′, —NR′S(O)₂NR′R′, —NR′—S(O)₂R′, —NR′C(O)R′,—S(O)₂—NR′R′ and —NR′R′ (where each R′ is independently selected fromhydrogen, lower alkyl, C₃-C₇cycloalkyl, heterocyclyl, heteroaryl, —OH,or NH₂), —S(O)R″ (where R″ is lower alkyl, or cycloalkyl), —S(O)₂R′″(where R′″ is lower alkyl, or cycloalkyl), or any two adjacent R_(1a)together form heterocyclyl or heteroaryl; m is 0-5; R₂ is selected fromC₁-C₄ alkyl, C₁-C₄ haloalkyl, phenyl, F, or Cl; R₃ is selected fromhydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, F, Cl, or CN; or R₂ and R₃together form C₄₋₉ cycloalkyl or C₄₋₉ cycloalkenyl; R₄ is selected fromoptionally substituted heteroaryl, optionally substituted heterocyclyl,or optionally substituted aryl; R₅ is independently selected fromhydrogen, or C₁-C₄ alkyl; and n is 1-3. 26-28. (canceled) 29) A compoundaccording to claim 25 or a salt thereof, wherein R₄ is

wherein one of Hal is —H and the other is a halogen; p is 0, 1, 2, or 3;and each R₉ is independently selected from halogen, CN, NO₂, haloalkyl,aryl, heteroaryl, C₁₋₆ alkoxy, C₁₋₃ haloalkoxy, C₁₋₃ alkyl, or CO₂R′(where R′ is a lower alkyl or H).
 30. (canceled) 31) A compoundaccording to claim 25 or a salt thereof, wherein m is 1 and R_(1a) isselected from: —S(O)₂R′″ (where R′″ is lower alkyl, or cycloalkyl),—S(O)₂NR′R″ (where R′ is hydrogen and R″ is selected from hydrogen,lower alkyl, —OH, or NH₂), lower alkyl, substituted 1 or 2 times with asubstituent group selected from CF₃ and NH₂, lower haloalkyl, optionallysubstituted heterocyclyl (preferably 4 or 5-membered heterocyclyl),—NR′S(O)₂NR′R′ (where each R′ is independently selected from hydrogen orlower alkyl, C₃-C₇ cycloalkyl, heterocyclyl, or heteroaryl), or—NR′—S(O)₂R′ (where each R′ is independently selected from hydrogen orlower alkyl, C₃-C₇ cycloalkyl, heterocyclyl, or heteroaryl). 32) Acompound according to claim 31 or a salt thereof, wherein R_(1a) isselected from:

33-34. (canceled) 35) A compound according to claim 25 or a saltthereof, wherein

36) (canceled) 37) A compound according to claim 1 or a salt thereof,represented by the following:

an enantiomerically pure single trans-enantiomer or a mixture oftrans-isomers of any thereof. 38-40. (canceled) 41) A compound accordingto claim 1 or a salt thereof, wherein the compound is present as: (i) amixture of cis-isomers; (ii) a mixture of trans-isomers; or (iii) anenantiomerically pure single trans-enantiomer.
 42. (canceled) 43) Apharmaceutical composition that comprises a therapeutically effectiveamount of one or more compound of claim 1 or pharmaceutically acceptablesalts or pharmaceutically acceptable derivatives thereof, and optionallya pharmaceutically acceptable carrier or diluent. 44) A method for: (i)ameliorating treating or preventing cognitive deficits associated withneurodegenerative and neuropsychiatric diseases; (ii) preventing ortreating neurodegenerative or neuropsychiatric disorders; (iii)treatment or prevention of inflammatory diseases; or (iv) treatment orprevention of neuropathic pain, said method comprising administering atherapeutically effective amount of one or more positive allostericmodulators of α7 nAChRs compounds of claim 1, or a salt orpharmaceutically acceptable derivative thereof. 45-49. (canceled) 50) Aprocess for preparing a compound of formula (I) or salt thereof

wherein R₁-R₆ are as defined in claim 1, R₇ and R₈ are H, and n is 1,said process comprising the step of reducing a compound of formula (II)


51. (canceled) 52) A process according to claim 50 wherein said compoundof Formula II is reduced by contact with a borane tetrahydrofurancomplex. 53) A process for preparing a compound of formula (I) or saltthereof

wherein R₁-R₆ are as defined in claim 1, R₇ and R₈ are H, and n is 1 or2, said process comprising the step of reacting a compound of formula(III), (IV) or (V)

with an amine of formula NHR₅R₄.